Volume 4, Issue 2, Pages 47-61 (April 2006)

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ABSTRACT

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Efficacy of Interstitial Cystitis Treatments: A Review

Abstract

Objective

Interstitial cystitis (IC) is a chronic clinical condition known for more than a century. Its pathophysiology remains largely unclear. No universally-effective treatment exists, and many patients do not respond to available therapies. There is no evidence-based algorithm and no standard therapy for IC. The aims of this article are to review the available treatment options and to evaluate the degree of evidence regarding their clinical efficacy.

Materials and Methods

We reviewed English language publications on IC from January 1966 to August 2005 listed in MEDLINE, and we selected clinical studies reporting on IC treatment. For each treatment type, we give the level of evidence and the recommendation grade according to the “Oxford University Program for Evidence-based Studies”.

Results

Most articles were retrospective, non-randomized, uncontrolled studies with small numbers of patients. Twenty articles provided high-level evidence. Three therapies are supported by a high level of evidence: oral Cimetidine and Amitriptyline, and one intravesical agent, Dimethylsulfoxide (DMSO). Reports on surgical treatments were only open investigations.

Conclusion

IC treatment is complex and controversial because of the disease's unidentified, formal etiology. We proposed an evidence-based algorithm that might be helpful when counseling IC patients regarding treatment options and expectations from each therapy.

Keywords: Interstitial cystitis, Treatments, Evidence-based medicine, Amitriptyline, Cimetidine, DMSO

Article Outline

• Abstract

• 1. Introduction

• 2. Materials and methods

• 3. Results

• 3.1. Oral therapies ()

• 3.1.1. Antihistaminics

• 3.1.2. Amitriptyline (Elavil, Endep)

• 3.1.3. -Arginine

• 3.1.4. Pentosanpolysulfate (PPS) (Elmiron)

• 3.2. Other oral therapies ()

• 3.3. Intravesical therapy ()

• 3.3.1. Prolonged hydrodistention

• 3.3.2. Dimethylsulfoxide (DMSO)

• 3.3.3. Heparin

• 3.3.4. Bacillus Calmette-Guerin (BCG)

• 3.3.5. Hyaluronic acid (HA)

• 3.3.6. Sodium oxychlorosene (Clorpactin WCS-90)

• 3.3.7. Resiniferatoxin (RTX)

• 3.3.8. Intravesical injections of Botulinum Toxin A (BTA)

• 3.4. Surgical treatment ()

• 3.4.1. Neuromodulation

• 3.4.2. Transurethral ablative treatments

• 3.4.3. Trans-urethral resection (TUR)

• 3.4.4. Laser fulguration

• 3.4.5. Cystectomies and reconstructions

• 3.5. Bladder augmentation combined with partial cystectomy. ()

• 3.5.1. Urinary diversion

• 3.6. Multimodal treatments ()

• 4. Conclusions

• Appendix A. Evidence Levels and Recommendation Grades

• A.1. Evidence Levels

• A.2. Recommendation Grades

• References

• Copyright

1. Introduction

The designation “interstitial cystitis” (IC) has been used for more than a century to describe a complex voiding dysfunction [1]. In 1914, Hunner [2], [3] published his findings on bladder ulcers that still bear his name.

IC is a syndrome characterized by bladder pain associated with urgency, frequency, nocturia, dysuria, and sterile urine. Diagnosis is based on the patient's symptomatology and urological evaluation, including cystoscopy, urodynamic study, and exclusion of other recognizable bladder diseases [3]. Severity can be assessed with self-administered validated questionnaires like the O’Leary-Sant Interstitial Cystitis Symptom and Problem Index or the University of Wisconsin Symptom Score [4], [5].

IC is usually classified into 2 categories, “classic” (with Hunner's ulcers), observed in 5–20% of patients [6], and “non-ulcer” based on cystoscopy. To standardize the diagnosis of IC for research purposes, the National Institute of Diabetes, Digestive and Kidney Diseases defined its symptoms [7]. However, less severe and early IC can be missed when only these criteria are considered.

Although bladder permeability defects, autoimmunity, infection, genetics, neurological and hormonal factors or the effects of toxic substances in urine have been postulated, the actual etiology of IC remains unclear [8].

Because disease mechanisms remain largely unknown, current goals of IC treatments are limited to symptom improvement.

The number and variety of treatment modalities reported at baseline in women enrolled in the International Cystitis Data Base Study [9], 183 treatments for 581 patients, reflect the wide range of ineffective therapies currently offered to IC patients on an empirical basis.

The aims of this review are (a) to give an overview of IC treatments reported in the literature; (b) to evaluate the level of evidence supporting each modality; and, accordingly, (c) to propose a “Recommendation grade” for each of them.

2. Materials and methods

MEDLINE was searched for articles published between 1966 and July 2005, using “interstitial cystitis”, and “treatment” as key words. English-written papers reporting clinical trials of IC treatments were selected. A second selection identified articles reporting controlled clinical trials for further analysis. The results of non-controlled trials were briefly cited, except when no controlled trial for a modality was available. We defined the level of evidence for each modality, and formulated our recommendations according to the “Oxford Centre for Evidence-Based Medicine Levels of Evidence” (Appendix A) [10].

3. Results

77 publications on clinical trials of IC treatments were found, twenty were controlled clinical trials synonymous with a level of evidence higher than 4.

3.1. Oral therapies (Table 1)

3.1.1. Antihistaminics

Histamine, a substance released by mast cells, can induce pain, vasodilatation and hyperemia. The infiltration and activation of mast cells within the bladder wall have been postulated to play a role in the pathogenesis of IC [11], [12]. This was the rationale for using antihistaminics to treat IC.

Table 1.

Summary of evidence levels and recommendation grades for common oral IC therapies


Medication	Evidence level	Recommendation grade	Use (+) Do not use (–)
Cimetidine	1 (efficacy)	B	(+)
Amitriptyline	1 (efficacy)	B	(+)
Pentosanpolysulfate	Conflicting data, no recommendation (or grade D)
Hydroxyzine	1 (no major efficacy)	B	(−)
l-Arginine	1 (no major efficacy)	A	(−)

Hydroxyzine is a heterocyclic piperazine histamine 1 receptor antagonist. Theoharides [13] first reported 37/40IC patients who benefited from Hydroxyzine 25–75mgperday. Theoharides and Sant [14] reported, in 90 patients, still without controls, an average 40% reduction of symptoms with 25–75mg Hydroxyzine daily for 3 months.

The study by the Interstitial Cystitis Clinical Trials Group (ICCTG) [15], provides a high level of evidence for the inefficacy of oral Hydroxyzine as a single therapy of IC. 121 patients from 7 centres were randomized to receive either placebo or oral Hydroxyzine or oral Pentosanpolysulfate (PPS) or an oral combination of Hydroxyzine and PPS. The primary endpoint was patient-reported global response assessment after 24 weeks compared to baseline. Intent-to-treat analysis was undertaken. There was no significant difference between the Hydroxyzine (31%) and no Hydroxyzine (20%) groups.

To date, we conclude that evidence level-1b applies in view of the absence of major improvement in IC symptoms under oral Hydroxyzine alone. The lack of analytical power of these studies (1,000 patients would be required to provide adequate statistical power to detect differences in the range of those observed) does not allow us to conclude that Hydroxyzine had no effect at all on IC symptoms. If such an effect occurs, it is likely to be minor (less than 50% response rate which was considered by the ICCTG as being clinically meaningful). Recommendation grade B to not administer Hydroxyzine in usual clinical practice.

Cimetidine is a histamine-2 antagonist. Two uncontrolled studies, respectingly involving 9 and 69 patients [16], [17], were the first to report that 66 and 74% of patients experienced symptom relief under oral Cimetidine (300mg twice daily) over a period of 30 months.

The clinical effect of Cimetidine (400mg twice daily) was confirmed in a prospective, randomized, double-blind, placebo-controlled trial in 34 patients with non-ulcerative IC [18]. A validated questionnaire scored symptoms of frequency, urgency, suprapubic pain, nocturia and dysuria from 0 to 5 according to severity. Decreases in global symptom severity scores were significantly higher in the treated group (19.7 to 11.3) compared to the placebo controls (19.4 to 18.7). Suprapubic pain and nocturia were the most improved symptoms.

Evidence level 1c supports the efficacy of Cimetidine to relieve IC symptoms. Grade B recommendation for its use to treat IC.

3.1.2. Amitriptyline (Elavil®, Endep®)

Amitriptyline is a tricyclic antidepressant. It exerts central and peripheral anticholinergic activity, has antihistamine sedation effects, and inhibits serotonin and norepinephrine reuptake.

Hanno et al., in 1989, first reported improvement in pain and daytime frequency in 95% (19/20) of patients treated with Amitriptyline [19]. 8 patients experienced total remission, and 11 were improved. Recently, van Ophoven et al. [20] reported on the safety and efficacy of a 4-month self-titrated Amitriptyline regimen (25–100mg daily) in a randomized, placebo-controlled study involving 50 patients. Mean symptom score decreased from 26.9 to 18.5 in the Amitriptyline group compared with 27.6 to 24.1 in the placebo group (p=0.005). Pain and urgency intensity were also significantly improved with Amitriptyline compared to placebo. Frequency and functional bladder capacity improved to a much greater degree in the Amitriptyline group, but not significantly in comparison to placebo.

Evidence level 1b supports Amitriptyline efficacy to treat IC. Recommendation grade B for its use. Since long-term efficacy is highly expected in chronic disease treatment, there is a need for data on efficacy and safety of long-term Amitriptyline to treat IC.

3.1.3. l-Arginine

Nitric oxide, the product of nitric oxide synthetase (NOS), increases relaxation of the smooth muscle. Decreased urinary NOS activity has been reported in IC patients. l-Arginine, a substrate for NOS, has been thought to improve IC symptoms [21].

Two randomized, placebo-controlled, double-blinded trials respectively involving 46 and 16 patients investigated the efficacy of l-Arginine for IC treatment [22], [23]. Both of them found no difference in IC symptoms under l-arginine 1.5 to 2.4g daily or placebo at 3 months. Evidence level 1b supports the absence of major efficacy of oral l-Arginine alone to treat IC. A grade A recommendation is given to not administer it in IC. However, the limited analytical power of these studies due to the sample size does not allow us to exclude any effect of oral l-Arginine. If such an effect occurs, it is likely to be minor and not clinically meaningful.

3.1.4. Pentosanpolysulfate (PPS) (Elmiron®)

Glycosaminoglycan (GAG), a part of the normal bladder epithelium, protects the bladder from harmful urinary components. One of the hypotheses regarding IC is that a defect in this layer allows the diffusion of irritating components within the bladder wall [24].

PPS, a synthetic sulfated polysaccharide, has been developed in oral form that is excreted in urine to correct GAG layer defects. The recommended dosage is 100mg times a day. Six double-blind, placebo-controlled studies have examined PPS effectiveness for IC treatment. Parsons and Muholland [25] undertook a crossover trial in 62IC patients who were given 300–400mg of PPS for a period of ≥4 months. They reported >50% improvement in frequency, nocturia, urgency and pain with PPS compared to placebo. The same investigators conducted another placebo-controlled study in 110 patients receiving 300mg PPS for 3 months [26]. They observed more than 25% improvement of overall symptoms in 28% of patients taking PPS vs. 13% for placebo. A third prospective trial in 148 patients on 300mg PPS or placebo for 3 months [27] reported 50% or greater improvement on a subjective rating of symptoms in 32% and 16% of patients taking PPS and placebo respectively. They concluded that PPS was more effective than placebo in the treatment of pain, urgency, and frequency, but not in improving nocturia. Lately, Nickel et al. compared 3 dosages of PPS (300, 600 and 900mg daily) in a randomized trial involving 380 patients followed 32 weeks [28]. Efficacy was evaluated on the O’Leary-Sant Symptom Index and on the Patient's Overall Rating of Symtom index (PORIS) there was no control group. Response was defined as 50% or greater improvement on PORIS Both indices were improved, but no difference between doses was found. At 32 weeks 45 to 49% patients were responders. The authors concluded that the duration of therapy was more important than dosage. These 4 studies provide level 1b to 4 evidence for PPS efficacy in relieving IC symptoms. Only short-term efficacy (3 to 4 months) was evaluated.

Holm-Bentzen et al. [29] evaluated 400mg PPS over 4 months in a multicentre, randomized, placebo-controlled study. Symptoms, urodynamics, cystoscopic aspects and histology were compared in 115 patients. Except for cystoscopically-determined bladder capacity, no significant difference was apparent between the PPS and placebo groups.

The ICCTG compared 6 months PPS and Hydroxyzine to placebo to examine their utility as stand-alone treatments and as combinations [15]. 121 participants were randomized over 18 months, with 79% providing complete follow-up data. The primary endpoint was patient-reported global response assessment. Secondary endpoints included validated symptom indices, and patient estimation of pain, urgency and frequency. The response rate was 31% for the Hydroxyzine group vs. 20% for those not treated (p=0.26), and 34% for the PPS group vs. 18% for placebo (p=0.064). Combined PPS+Hydroxyzine treatment demonstrated the highest response rate (40%), but was neither significant nor analyzed in an intent-to-treat way. As underlined by the authors the results should be interpreted with caution because of the bias in withdrawal from the study. The Holm-Bentzen and Sant trials provide level 1b evidence against the major efficacy of 4 to 6 months of oral PPS alone to relive IC symptoms. Conflicting findings with comparable levels of evidence do not allow us to draw conclusions on the utility of PPS alone (recommendation grade D to use or not to use). If PPS does have a positive effect, it is likely to provide only modest measurable improvement in 28–49% of treated patients. Such conflicting data preclude evidenced-based-recommendations on PPS in IC (or grade D to use or not to use).

3.2. Other oral therapies (Table 2)

Table 2 summarizes the results obtained with various other oral drugs in pilot studies without control subjects.

Table 2.

Summary of evidence levels and recommendation grades


Medication (references)	Mechanism	N	Follow-up (months)	Results	Evidence level	Recommendation grade (to use)
Nifedipine [93]	Calcium channel antagonist	9	3	5 improved	4	C
				3 asymptomatic
				1 failed

Misoprostol [94]	Oral prostaglandin	25	3–6	14 improved significantly	4	C
				12 sustained response

Oral Methotrexate [95]	Immunosuppression	9	6	4 improved	4	C
				4 little change
				1 symptoms worsened

Montelukast [96]	Cysteinyl leukotriene	10	3	10 significant reduction of frequency and pain	4	C
	D4receptor antagonist

Prednisone [97]	Immunosuppression	14	16 (Ulcerative IC)	9 significant reduction of pain	4	C

Cyclosporin Aa [98], [99]	Immunosuppression	11–23	6–12 (Refractory IC considered for surgery)	Decreased bladder pain	4	C
				Voids/24h: 20.8 to 10.
				Bladder capacity 161.8 to 360.7ml Voided volume 101.4 to 246.4ml

Hyperbaric oxygenb [100]	Tissular hyperoxygenation	6	12	4 decrease in pain, nocturia, frequency and increased functional capacity	4	C

CystoProtek [101]	Flavonoid quercetin+chondroitin sulfate	37	6	Significant improvement of O’Leary Symptom Index and Global Assessment Scale	4	C

In both studies, the number of void /24h, bladder capacity and mean voided volume were statistically improved. We report the values of the larger and longer study.

Although hyperbaric oxygen is not an oral therapy, we consider it as a systemic therapy and present its results with those of oral drugs.

3.3. Intravesical therapy (Table 3)

3.3.1. Prolonged hydrodistention

The effect of hydrodistention on IC symptoms was reported early [30]. Ischemic necrosis of the sensory nerves within the bladder wall was first postulated to explain its action [31], more recently increased urinary levels of heparin-binding epidermal growth factor, decreased anti-proliferative activity [32] and changes in bladder microvascularization have been proposed [33].

Table 3.

Summary of evidence levels and recommendation grades for common intravesical IC therapies


Treatment	Evidence level	Recommendation grade	Use (+) do not use (−)
Prolonged hydrodistension	4	C	(+)
DMSO	1	B	(+)

Heparin
Single therapy	4	C	(+)
Maintenance after DMSO	1	B	(+)

BCG	1 (no efficacy)	A	(−)
Hyaluronic acid	4	C	(+)
Clorpactin	4	C	(+)
Resiniferatoxin	1 (no efficacy)	B	(−)
Botulinum toxin-A	4	C	(+)

Dunn et al., reported symptom improvement for 3 to 5 months after prolonged hydrodistention in 16/25IC patients [34]. McCahy and Styles noted that 3/7IC patients found the procedure “worthwhile” [35]. Hydrodistension was performed discontinuously in these 2 studies (3 or 4 30-min periods with 5-min rest intervals).

Glemain et al. [36] reported the largest study to date, on 65 consecutive IC patients without controls. Hydrodistention was performed continuously for 3h without rest intervals under epidural anesthesia, using a balloon with pressure equal to the patients’ mean arterial pressure. Efficacy was defined as the disappearance of pain on bladder filling or the persistence of moderate, non-disabling pain (for which the patient did not request treatment) and a low frequency of nocturia (0 to 2 times). For the retrospective part of the study, treatment efficacy was 12/32 (37.7%) at 6 months and 7/32 (21.9%) at 1 year. For the prospective part of the study, efficacy was 18/30 (60.0%) at 6 months and 13/30 (43.3%) at 1 year. The results were better for patients with bladder capacity exceeding 150ml during cystometrograms before distension.

Evidence level 4. Recommendation grade C.

3.3.2. Dimethylsulfoxide (DMSO)

An anti-inflammatory effect, alteration of the collagen response, and influence on conduction and neurotransmission in sensory nerves, especially C fibres, has been postulated as the mechanism of DMSO action [37], [38]. High concentrations (50%) are instilled every 1–2 weeks in 4 to 8 treatments, depending on the physician's choice. DMSO induces a transient garlic odour, with initial worsening of symptoms in 10–15% of patients.

3 uncontrolled trials found that it improves IC symptoms in 50%–70% of patients at a 50% concentration [39], [40], [41]. Sant [42] followed 22 patients over 24 months and found a 40% relapse rate after 4 treatments. Perez-Marrero et al. [43], in a placebo-controlled, crossover trial of 33 patients, reported objective symptom improvement based on urodynamic data, a 48-h voiding diary, and VAS assessment for frequency, urgency, and pain. After 4 treatments, all parameters were improved in 93% of patients receiving DMSO compared to 35% in the placebo group. However, the recurrence rate after treatment cessation was 59%.

To decrease the recurrence rate, the same investigators [44] conducted a randomized, controlled trial in 50 patients divided into 2 groups: the first received 10,000IU of intravesical heparin every month for 12 months post-DMSO, and the second group was treated with DMSO alone. They observed that only 20% of 25 patients in the heparin- treated group relapsed, as defined by the recurrence of symptoms necessitating additional therapy, compared to 52% of 25 patients in the DMSO group. Evidence level 1b. Recommendation grade B.

3.3.3. Heparin

Since alteration of the urothelial GAG layer is one of the hypotheses of IC pathophysiology, and heparin is known to mimic the GAG layer structure, there is a rationale for local administration of heparin to treat IC [45]. Moreover, heparin has anti-inflammatory effects and inhibits angiogenesis and proliferation of fibroblast and smooth muscle. Parsons et al. [46] reported on 48IC patients treated with intravesical heparin (10,000IU) 3/week for 3 months. At 3 months, 27 (56%) of the 48 patients were improved based on a 3-day voiding diary and cystometrograms. Responders were offered continuous therapy. Of the 23 who opted for an additional 3 months, 20 remained in remission. 15 had another 6 months of treatment and stayed in remission. The authors concluded that intravesical heparin controlled IC symptoms in more than 50% of patients; even after 1 year.

Kuo [47] treated 40IC patients suffering severe IC symptoms, with 25,000UI of heparin twice a week for 3 months. 29 patients showed symptom score improvement of >50%, and 8 had symptom score amelioration of <50% but with nocturia correction. Urodynamic evaluation at the end of treatment revealed significant improvement in the first sensation of filling and cystometric capacity.

As mentioned earlier, intravesical heparin can be seen as maintenance therapy post-DMSO, or as a part of multimodal therapy (multimodal treatment, Table 4).

Table 4.

Summary of evidence levels and recommendation grades for surgical procedures to treat IC


Treatment modality	Evidence level	Recommendation grade use (+), not use (−)
Neuromodulation	4	C (+)
Transurethral resection (in ulcer IC)	4	C (+)
Laser fulguration (in ulcer IC)	4	C (+)
Partial Cystectomies and bladder augmentation (in IC refractory to conservative options)	Contradictory data 4	No recommendation
		or
		Grade D for both (+)(−)
Urinary diversion (In IC refractory to conservative options, selected cases.)	4	C (+)

Evidence level 4 supports the efficacy of intravesical heparin as a main therapy to treat IC (monotherapy). Recommendation grade C.

Evidence level 1b supports the efficacy of intravesical heparin as a maintenance therapy, after successful intravesical DMSO. Recommendation grade B.

3.3.4. Bacillus Calmette-Guerin (BCG)

Pathophysiology hypotheses of IC include immune system dysregulation with a possible imbalance between Th1 and Th2 cells. Intravesical BCG is an immunological therapy for superficial bladder tumor, and is known to stimulate the Th1 cytokine profile. Thus intravesical BCG has been advocated as an option for IC treatment [48].

Peters et al. reported a randomized prospective trial in 30 patients who received weekly instillations of BCG or placebo for 6 weeks [49]. Mean follow-up was 8 months. Periodic questionnaires, voiding diaries and cystometrograms were recorded. Based on the exit questionnaire, a “responder” was defined as having IC symptoms moderately improved or better. They obtained a 60% BCG response rate compared to 27% in the placebo arm, but this difference did no reach significance (p=0.06). At long-term follow-up (27 months) 89% of the “responders” continued to have an excellent response on all parameters [50]. Overall well-being was observed in 54% of cases with improvement in 64% of patients on the Rand-36 Quality of Life Survey.

Peeker et al. [51] conducted a prospective, double-blind study with a crossover design, comparing intravesical BCG and DMSO to determine whether patients with classic and non-ulcer IC might benefit from either regimen. A total of 21 patients, 11 with classic and 10 with non-ulcer IC, randomly underwent treatments with intravesical BCG or DMSO, and if not improved, were given the other medication after a washout period. Regardless of the regimen, there was no improvement in maximal functional capacity. Urinary frequency decreased after DMSO treatment but only in the classic subtype, whereas no reduction was seen after BCG in either subtype. Pain was diminished in classic as well as non-ulcer IC after DMSO only.

The ICCTG recently reported the results of a multicentre, randomized, double-blinded, placebo-controlled trial on intravesical BCG for the treatment of refractory IC [52]. 265 patients were enrolled; sample size was calculated to detect a difference of 30 and 50% in the response rates between placebo and BCG. The primary outcome was patient-reported global response assessment at 34 weeks; secondary outcomes were 24-h voiding diary, pain, urgency, the validated IC symptoms index (O’Leary-Sant and the University of Wisconsin Index), and adverse events. Patients were suffering moderate to severe IC. The difference between the response rate in the BCG group (21%) and the placebo group was found to be not significant (12%).

Although Peters et al. observed a difference in favour of BCG, it was not statistically significant, and thus provided only evidence level 5 (trend or expert opinion) toward efficacy of BCG. In contrast the ICCTG trial had a high power of analysis; adapted to the range of difference and provided evidence level 1b against the efficacy of BCB. We concluded that Evidence level 1b supports the absence of efficacy of intravesical BCG to treat IC. Recommendation grade A to not use.

3.3.5. Hyaluronic acid (HA)

HA; a non-sulfated mucopolysaccharide component of the GAG layer with a preponderant concentration in sub-epithelial connective tissue [53], [54], is thought to protect the bladder wall from the irritating effects of urine. HA might also work as a scavenger of free radicals and as an immune modulator [55]. Morales et al. [56] investigated the efficacy of a weekly intravesical dose of 40mg HA for 4 week, in a group of 25IC patients refractory to previous medical treatments. The response rate was evaluated on symptom score, voiding diary, and VAS (urgency and pain). Improvement was defined as more than 50% reduction in symptom score, urgency and pain. Improvement rate increased from 56% at 4 weeks, to 71% at 12 weeks and was maintained until week 20. Effectiveness decreased beyond week 24. No significant toxicity was attributed to HA.

Porru et al. [57] investigated the efficacy of 40-mg HA weekly instillations in 10 patients after 6 weeks of treatment. Pre-treatment and post-treatment symptom scores were comparedand voiding diaries evaluated the response to therapy. 3 patients had partial improvement at week 6. Responders were given maintenance therapy monthly for 6 months; their response was maintained until week 24. Nordling et al. [58], [59] undertook a prospective, non-randomized study on the efficacy of HA with 3-year follow-up in 20 patients with symptomatic IC. They administered 40mg HA weekly for a month, then at 2 months and 3 months. After the completion of initial treatment, patients chose to stop or continue with monthly instillations based on subjective clinical effects. They were evaluated by voiding diary and pain scale. Eleven patients chose to continue their treatment. Seven had been treated for a mean of 37 months and experienced continuing improvement in pain and frequency.

Evidence level 4. Recommendation grade C

3.3.6. Sodium oxychlorosene (Clorpactin WCS-90)

Sodium oxychlorosene is a mixture of hypochlorous acid and the sodium salt of dodecylbenzene sulfonic acid. It might exert a detergent action on the bladder mucosa; its sulfonic acid promotes hypochloride penetration with a germicidal effect [60].

Clorpactin is administered under anesthesia because its intravesical instillation is painful. Vesico-ureteral reflux is a contraindication because of ureteral fibrosis risk. The perineum and vulva have to be protected from contact with Chlorpactin to avoid burns [61]. Messing and Stamey [62] treated 52 patients with a 0.4% solution administered at 10cm H2O pressure under anesthesia, with a 1-month pause after the first 2 instillations to wait for a therapeutic response. They reported success (more than 6 months of symptomatic improvement) in 72% of patients. Sant and LaRock [60] obtained 50–60% subjective improvement on symptom scores and global assessments in 60 patients after 0.4% Clorpactin treatment.

It should be noted that a recent study of bacterial and viral DNA in bladder biopsies of IC patients failed to provide any support for chronic infection as an etiologic factor in of IC [63].

Evidence level 4. Recommendation grade C.

3.3.7. Resiniferatoxin (RTX)

RTX, a vanilloïd neurotoxin, might be an effective agent for patients with IC by desensitizing bladder C-fibers that transmit painful stimuli and produce urinary frequency and urgency. Lazzeri et al. [64] published a pilot study of 5 patients, reporting the feasibility and efficacy of continuous intravesical RTX infusion. Payne et al. undertook a multicentre, randomized, placebo-controlled trial to assess the efficacy and safety of single-dose RTX to treat IC [65]. 163 patients from 30 centres were evaluated at 1, 4, 8, and 12 weeks. The primary efficacy endpoint was a 7-points scale to assess the global response. Secondary endpoints were reduction in pain, urgency, frequency, nocturia, average voided volume and the O’Leary-Sant questionnaire. Unlike Lazzeri et al. [64], they reported no difference between any treatment groups (10, 50, 100nm RTX) compared to placebo. Additionally, RTX instillation resulted in a dose-dependent increase of pain as confirmed by Chen et al. in a placebo-controlled study on RTX safety and tolerability in IC [66].

Level 1 evidence supports the inefficacy of a single intravesical RTX dose to treat IC. Recommendation B to not use. Other administration modes are still in the clinical research phase.

3.3.8. Intravesical injections of Botulinum Toxin A (BTA)

BTA is a recent option for IC treatment. It inhibits acetylcholine release at pre-synaptic neuromuscular junctions [67]. An antinociceptive effect of BTA, has been also proposed [68]. Schurch et al. [69] first demonstrated efficacy and safety of BTA injections to treat neurogenic incontinence. Smith et al. described the first experience with intradetrusor BTA injections to treat IC patients [70]. Out of 13 patients, 9 had symptom improvement within the first week after injections of 100 to 200 units. At 3 months, the mean Interstitial Cystitis Symptom Index score and the Interstitial Cystitis Problem Index score improved by 71% and 69%, respectively. Daytime frequency, nocturia, and pain evaluated by VAS decreased by 44%, 45%, and 79%, respectively. First desire to void and maximal cystometric capacity increased by 58% and 57%, respectively.

Evidence level 4. Recommendation grade C

3.4. Surgical treatment (Table 4, Table 5)

When oral or intravesical conservative management of IC fails, various surgical techniques have been proposed. All but sacral neuromodulation are destructive and irreversible.

3.4.1. Neuromodulation

Sacral neuromodulation (SNM) has been first thought to be useful to improve IC symptoms because it efficacy has been demonstrated in improving urgency, frequency and urge incontinence [71], [72]. SNM is thought to act via the stimulation of somatic afferents which inhibit the transmission of afferent messages arising from the bladder [73]. Maher et al. [74] first tried subchronic SNM to treat IC symptoms in 15 patients. During treatment, mean voided volume improved as did pain, daytime frequency and nocturia.

Comiter et al. [75] applied SNM in 25 patients with refractory IC. Patients were evaluated by voiding diary, reports of average pain, the IC Symptom Index, and the IC Problem Index. 17/25 achieved 50% or greater symptom reduction during subchronic testing and were qualified for permanent implantation. At 14 months follow-up, significant improvement was noted in mean daytime frequency and nocturia, from 17.1 to 8.7 and 4.5 to 1.1, respectively. Mean voided volume increased significantly from 111 to 264ml, and average pain decreased from 5.8 to 1.6 points. Peters et al. [76] reported outcomes of SNM in 37IC patients who were evaluated with VAS, questionnaires and voiding diaries. 26 of 37 patients were permanently implanted and showed a 51% reduction in 24-h voids. More than two-thirds of patients reported moderate or marked improvement in urinary frequency, urgency, pelvic pain, pelvic pressure, incontinence and quality of life. The same authors also reported a significant decrease in narcotic requirements after chronic SNM [77].

Technical variants of the SNM technique (Interstim® therapy, Medtronic), such as tibial nerve stimulation alone, had no effect on IC patient symptoms [78], [79], [80].

Evidence level 4. Recommendation grade C.

3.4.2. Transurethral ablative treatments

As early as 1918, Hunner [81] proposed trans-urethral electrical fulguration to treat bladder ulcers.

3.4.3. Trans-urethral resection (TUR)

Peeker et al. [82] recently reported their results with 259 TURs in 103 patients with classic ulcerative IC. After TUR, 92 individuals experienced considerable amelioration, with 40% reporting symptom relief lasting more than 3 years. In the remaining patients, although symptom recurrence was common, the majority responded well to subsequent TUR.

Evidence level 4 in ulcer IC. Recommendation grade C.

3.4.4. Laser fulguration

Repeat TUR of ulcers may lead to bladder contracture. Laser fulguration of ulcers may avoid significant bladder scarring and contracture despite multiple treatments. Neodymium-YAG (ND-YAG) surgery was a first reported in 1985 by Shanberg et al. [83]. Malloy and Shanberg [84] treated 76 patients with IC refractory to other treatments: 27 had Hunner's ulcers, and 49 had glomerulations and inflammation. Of the 27 patients with Hunner's ulcers, 78% felt immediate pain relief, but 12 (48%) developed recurrent symptoms within an 18-month period. Of the 49 patients with glomerulations and inflammation, 33% showed marked improvement of their pain and frequency symptoms after laser therapy. They concluded that laser treatment was more efficient in ulcerative IC. Rofeim et al. [85] treated 24 patients with ulcerative IC refractory to medical therapy with 23 months follow-up. All patients presented symptom improvement within 2–3 days. Pain, urgency, voiding interval and voids/night were significantly improved. 13 patients had 1 treatment, and the mean duration of effect was 19 months. 11 patients required 1 to 4 additional treatments and the duration of relief was 6 to 9 months/treatment. The re-treatment response was similar to the initial treatment response. Importance of laser settings was emphasized: low energy (15W) for 1 to 3s [84], [85].

Evidence level 4 for efficacy in ulcer IC. Recommendation grade C

3.4.5. Cystectomies and reconstructions

The principle of ablative surgery in IC is to remove the tissue where the pathological process responsible for pain and urgency is supposed to be. To leave trigone and urethra expose patients to a risk of persistent or recurrent pain, urgency and frequency, after surgery. Moreover psychological pain or central sensitization can be another factor in failure of surgery in patients who have been suffering from IC for a long time.

Open surgery is considered in the management of IC patients only when all conservative options have failed [86].

3.5. Bladder augmentation combined with partial cystectomy. (Table 5)

23 case series reported on various techniques of partial cystectomy combined with intestinal bladder substitution/augmentation to treat refractory IC. The results were contradictory, ranging from 0% to 100% of patients cured or improved. The data were also too conflicting to know whether cystectomy should be supratrigonal or subtrigonal to prevent symptom recurrence. There is a trend toward low anatomical bladder capacity (capacity under anesthesia) is predictive of favourable outcomes. Differences in inclusion criteria and outcome measurements preclude any evidence-based comparison.

Table 5.

Summary of studies on partial cystectomies and intestinal substitution/augmentation to treat refractory IC


Authors	N. of pts	Type of surgery	Results % successa	FU (year)	Additional issue
Blaivas et al. [102]	7	IA without C	0% (0/7)	9	Simple augmentation is not enough to treat IC symptoms

Chakravati et al. [89]	11	SupraTC+IA	72% (8/11)	9	2 late recurrence at 4 and 6 years, required diversion

Van Ophoven et al. [103]	18	SupraTC+IA	83% (15/18)	4.5

Costello et al. [104]	5	SupraTC+IA	100% (5/5)	1.5

Peekers et al. [91]	13	SupraTC+IA	77% (10/13)	5	Low ABC associated with better outcomes
					Mast cells infiltration not associated with outcomes

Linn et al. [105]	23	17 SubTC+IA	14/17	7.5	SubTC vs SupraTC: no difference
		6 SupraTC+IA	6/6		Low ABC associated with better outcomes
			86% (20/23)

Chrismas et al. [106]	24	SubTC+IA	100% (24/24)	2.5

Smith et al. [107]	1	SubTC+IA		–	Urethral pain recurrence after SubTC

Hughes et al. [108]	32	28 SubTC+IA	78% (25/32)	2–11	Low ABC associated with better outcomes
		4 SupraTC+IA

Nurse et al. [90]	36	SupraTC+IA	66% (16/24)	np	Histology of trigone (mastocyt infiltration) allow to predict outcomes (better results if negative trigone)
		24 no preop histo.	83% (10/12)
		12 preop histo

Kontturi et al. [109]	12		83% (10/12)	4.7

Nielsen et al. [110]	8		25% (2/8)	0.8	Immediate failure
					Low ABC associated with better outcomes
					Histology of trigone not associated with outcomes

Webster et al. [111]	19		84% (16/19)	0.3	Low ABC associated with better outcomes

Freiha et al. [112]	6	IA alone	66% (4/6)	np

No study provided level of evidence higher than 4. Articles are sorted by date of publication from the latest (2005) to the earliest (1980).

ABC: anesthetic bladder capacity; IA: Intestinal augmentation; C: cystectomy; SuraTC: supratrigonal cystectomy; SubTC: sub trigonal cystectomy (removal of trigone).

According to each author's success criteria.

Contradictory level 4 evidences supports both the efficacy and inefficacy of cystectomy and intestinal bladder augmentation to treat refractory IC. Recommendation grade D.

3.5.1. Urinary diversion

Cysto-urethrectomy and urinary diversion (continent or not) is the ultimate option for the treatment of refractory IC, particularly in patients with urethral pain. Lotenfoe et al. [87] achieved an overall clinical success rate of 73% with cystectomy, urethrectomy and continent colonic urinary reservoir. The success rate was only 20% in 5 patients with bladder capacity exceeding 400 cc, but 88% in 17 patients with bladder capacity below 400 cc. Pre-operative assessment of pain to rule out psychological pain or central sensitization and psychological examination identified patients likely to fail with this major surgery. The efficacy of cysto-urethrectomy and diversion as a salvage therapy after failure of bladder augmentation was also reported [88], [89], [90], [91].

Evidence level 4. Recommendation grade C.

3.6. Multimodal treatments (Table 6)

IC etiology is thought to be multifactorial, multi-agent therapy might produce synergistic effects and better outcomes. Table 4 summarizes various multimodal approaches.

Table 6.

Summary of multimodal treatment for IC


Medication	Mechanism	N	FU months	Results	Evidence level/method	Recommendation grade use (+), not use (−)
Doxepin 75mg+Piroxicam 40mg Oral, C [113]	Antidepressant+Anti-inflammatory	37	3	26 Symtoms in remission	4 open study	C (+)
				6 Improved (pain frequency)
				>80% relapsed at cessation

PPS+Hydroxyzine Oral, C [15]	GAG protector+anti histamine	121	18	PPS+Hydroxyzine: 40% responder n=30	5 RCT (opinion based on ns results)	D (−)
				Placebo: 13% responder n=30
				ns

DMSO+Heparin to maintain DMSO effect (Intravesical) [44]	Heparin mimic GAG structure	50	12	20% relapse DMSO+heparin vs 52% relapse DMSO alone (p<0.05)	1 RCT	B (+) (maintenance therapy after succesful DMSO)

Heparin intravesical+Peripheral neuromodulation [80]	Heparin mimic GAG structure. Neuromodulation affects micturition reflexes	10	13	Global improvement on Wisconsin Pain Score and bladder maximum capacity (+50 to 55 cc)	4 open study	C (+)

Methyl prednisolone+DMSO+Heparin Intravesical [114]	Immunomodulator+Neuromodulator+GAG protector	25	12	23 Remission of symptoms	4 open study	C (+)
				Average duration 8.1 months

ns: non-significant; c: continuously; RCT: randomized, controlled trial.

4. Conclusions

In this review, we found that the efficacy of only 2 oral medications (Cimetidine and Amitriptyline), and 1 intravesical therapy (DMSO), were supported by a high level of evidence. Until well-designed, controlled trials reveal new avenues of treatment for IC, we propose a therapeutic algorithm (Table 7) based on evidence in patients suffering from IC. Other approaches should be reserved in case of failure of this algorithm and be part of clinical research protocols. This review highlights the lack of good level studies to support the efficacy of most of treatments proposed to IC patients. We fully endorse the recommendations made by Propert et al. [92] about how future studies on IC treatments can be improved. Since IC is a chronic disease the investigation of long-term outcomes of its treatments appears primordial. Because of a relatively low incidence of the disease and high rate of drop-out observed in major recent studies [15], national or international research groups on IC treatment are essential to conduct studies that fulfill such demanding criteria.CME questionsPlease visit www.eu.acme.org to answer the EU-ACME questions on-line. The EU-ACME credits will then be attributed automatically.

1.Amitriptyline as oral therapy for interstitial cystitis (IC):

A.its long-term efficacy is supported by level 1 evidence

B.its therapeutic dose in IC is 100

mg daily

C.is more efficient when associated with oral anticholinergic drugs

D.is a first-line therapy for IC

2.Various modalities of oral therapy for interstitial cystitis:

A.Pentosan polysulfate (PPS) is a recommended first-line treatment of IC

B.Cimetidine 300 to 400

mg daily improves IC symptoms.

C.Hydroxyzine and Cimetidine are both anti-histaminic drugs with similar effects.

D.Dietary manipulations are useless in the management of IC.

3.Intravesical treatments of IC:

A.The therapeutic effect of bladder hydro-distension depends on instilled volume

B.DMSO acts as a neuromodulator on neural pathways which convey bladder pain

C.DMSO gives urine a garlic odor

D.Instillations of heparin are proposed for patients refractory to DMSO

4.Which intravesical conservative therapy demonstrated its efficacy in reducing IC symptoms in preliminary, open, uncontrolled studies that was contradicted by randomized, placebo-controlled trial?

A.Chronic sacral neuromodulation.

B.Hyaluronic acid intravesical instillation

C.Botulinum toxin injections within the bladder wall

D.BCG intravesical instillation

5.Treatment of ulcerative interstitial cystitis:

A.ablation of ulcers improves bladder capacity but not pain

B.deep ulcer trans-urethral resection (TUR) ensures a better result on IC symptoms

C.ulcer resection gives a sustained relief in primary IC symptoms.

D.Holmium laser for ulcer fulguration needs high energy (45

6.Surgery to treat interstitial cystitis:

A.In terms of IC symptom relief, subtrigonal cystectomy gives better results than supratrigonal cystectomy

B.In IC patients refractory to conservative therapies, urethro-cystectomy ensures pain relief

C.Higher pre-op bladder capacity is predictive of better outcome of ablative surgery for IC

D.Ablative surgery is considered only in patients who failed IC management by conservative options.

Table 7.

Evidence based algorithm for IC treatment

	1st line therapeutic options
	Amitiptyline 25 to 100mg daily (self titration)
	or
	Cimetidine 300mg twice daily
	or
	DMSO intravesical
	and
	Heparin intravesical as maintenance of DMSO, if responder
	or
	Ablation of ulcer: TURP or Laser (according to physician's experience) if ulcer ICa

	2nd line therapeutic options
	Any grade C recommendation, offering a conservative option according to physician's choice and experience.

	3rd line therapeutic options
	Patients who failed 1st and 2nd line therapeutic options as defined above should be classified as refractory IC
	Either: Refer the patient to a clinical research group for inclusion in a trial investigating new conservative option.
	Or Consider ablative surgery. (diversion)

Additionally, every patient can be advised to control fluid intake and reduce cafein. A food inquest to identify potential trigger food might be useful. Nevertheless such advices are not supported by any evidences higher than level-4 [115].

Although ablation of ulcers was only supported by level 4 evidence, it was found to be the only therapeutic approach specific for ulcer IC.

Appendix A. Evidence Levels and Recommendation Grades

A.1. Evidence Levels

Level 1 incorporates Oxford 1a, 1b, 1c

1a/ Consistent randomized, controlled trials, or conclusive meta-analysis of level 1 trials.

1b/ Randomized, controlled trial (low alpha and beta risk, usually >20patients/arm).

1c/ Randomized controlled trial (higher alpha and beta risk, usually<20patients/arm).Level 2 incorporates Oxford 2a and 2b

2a/ Good quality prospective cohort studies (consistent series, cohorts from the same place and therapeutic modalities at the same time).

2b/ One good quality cohort study.Level 3 incorporates Oxford 3a and 3b

3a/ Good quality, retrospective case-control studies (consistent series) where a group of patients who have a condition are matched (for age, sex, etc.) by control individuals from the general population at the same place and therapeutic modalities at the same time.

3b/ One good quality retrospective case-control study, or lower level cohort study where cohorts come from different places or times.Level 4 includes good quality case series where a group of patients, all with the same condition/disease/therapeutic intervention, are described without matching controls, or lower level case-control study where cases and controls do not come from the same place or receive treatments at different times.Level 5 includes expert opinions based not on evidence but on personal experience, first principles (e.g., physiological or anatomical) or bench research.

A.2. Recommendation Grades

As with evidence levels, evidence grades may apply either positively (do the procedure) or negatively (do not do the procedure).Grade A: Several studies providing consistent level 1 evidence.Grade B: several studies providing consistent level 2 or 3 evidence or 1 study providing level 1 evidence.Grade C: One (or more) studies providing consistent level 4 evidence.Grade D: One or more publications providing level 5 evidence or contradictory conclusions supported by the same level of evidence (1 to 4).

References

[1]. [1]Tait L. Cure of chronic perforating ulcer by the formation of an artificial vesico-vaginal fistula. Lancet. 1870;2:738. MEDLINE

[2]. [2]Hunner GL. A rare type of bladder ulcer in women:report of cases. Tans South Surg Gynecol Assoc. 1915;27:247.

[3]. [3]Nigro DA, et al. Associations among cystoscopic and urodynamic findings for women enrolled in the Interstitial Cystitis Data Base (ICDB) Study. Urology. 1997;49:86–92. Abstract | Full-Text PDF (718 KB) | MEDLINE | CrossRef

[4]. [4]Goin JE, Olaleye D, Peters KM, Steinert B, Habicht K, Wynant G. Psychometric analysis of the University of Wisconsin Interstitial Cystitis Scale: implications for use in randomized clinical trials. J Urol. 1998;159:1085–1090. Abstract | Full Text | Full-Text PDF (632 KB) | MEDLINE | CrossRef

[5]. [5]O’Leary MP, Sant GR, Fowler FJ, Whitmore KE, Spolarich-Kroll J. The interstitial cystitis symptom index and problem index. Urology. 1997;49:58–63. Abstract | Full Text | Full-Text PDF (749 KB) | MEDLINE | CrossRef

[6]. [6]Ho N, Koziol J, Parsons CL. Epidemiology of interstitial cystitis. In: Sant GR editors. Interstitial cystitis. Philadelphia: Lippincott-Raven; 1997;p. 9.

[7]. [7]Gillenwater JY, Wein AJ. Summary of the National Institute of Arthritis, Diabetes, Digestive and Kidney Diseases Workshop on Interstitial Cystitis, National Institutes of Health, Bethesda, Maryland, August 28-29, 1987. J Urol. 1988;140:203–206. MEDLINE

[8]. [8]Nickel JC. Interstitial cystitis: a chronic pelvic pain syndrome. Med Clin North Am. 2004;88:467–481xii. Full Text | Full-Text PDF (252 KB) | MEDLINE | CrossRef

[9]. [9]Rovner E, et al. Treatments used in women with interstitial cystitis: the interstitial cystitis data base (ICDB) study experience. The Interstitial Cystitis Data Base Study Group. Urology. 2000;56:940–945. Abstract | Full Text | Full-Text PDF (126 KB) | CrossRef

[10]. [10]Phillips B, et al. Levels of evidence and grades of recommandation., Oxford centre for Evidence-based Medicine, http://www.cebm.net/levels_of_evidence.asp, 2001.

[11]. [11]Kastrup J, Hald T, Larsen S, Nielsen VG. Histamine content and mast cell count of detrusor muscle in patients with interstitial cystitis and other types of chronic cystitis. Br J Urol. 1983;55:495–500. MEDLINE | CrossRef

[12]. [12]Theoharides TC, Sant GR, el-Mansoury M, Letourneau R, Ucci AA, Meares EM. Activation of bladder mast cells in interstitial cystitis: a light and electron microscopic study. J Urol. 1995;153:629–636. Full Text | Full-Text PDF (4390 KB) | MEDLINE | CrossRef

[13]. [13]Theoharides TC. Hydroxyzine in the treatment of interstitial cystitis. Urol Clin North Am. 1994;21:113–119. MEDLINE

[14]. [14]Theoharides TC, Sant GR. Hydroxyzine therapy for interstitial cystitis. Urology. 1997;49:108–110. Abstract | Full-Text PDF (419 KB) | MEDLINE | CrossRef

[15]. [15]Sant GR, et al. A pilot clinical trial of oral pentosan polysulfate and oral hydroxyzine in patients with interstitial cystitis. J Urol. 2003;170:810–815. Abstract | Full Text | Full-Text PDF (85 KB) | MEDLINE | CrossRef

[16]. [16]Lewi H. Cimetidine in treatment of interstitial cystitis. Urology. 1995;45:1088. Full-Text PDF (121 KB) | MEDLINE | CrossRef

[17]. [17]Seshadri P, Emerson L, Morales A. Cimetidine in the treatment of interstitial cystitis. Urology. 1994;44:614–616. Abstract | Full-Text PDF (428 KB) | MEDLINE | CrossRef

[18]. [18]Thilagarajah R, Witherow RO, Walker MM. Oral cimetidine gives effective symptom relief in painful bladder disease: a prospective, randomized, double-blind placebo-controlled trial. BJU Int. 2001;87:207–212. MEDLINE | CrossRef

[19]. [19]Hanno PM, Buehler J, Wein AJ. Use of amitriptyline in the treatment of interstitial cystitis. J Urol. 1989;141:846–848. MEDLINE

[20]. [20]van Ophoven A, Pokupic S, Heinecke A, Hertle L. A prospective, randomized, placebo controlled, double-blind study of amitriptyline for the treatment of interstitial cystitis. J Urol. 2004;172:533–536. Abstract | Full Text | Full-Text PDF (66 KB) | MEDLINE | CrossRef

[21]. [21]Ehren I, Iversen H, Jansson O, Adolfsson J, Wiklund NP. Localization of nitric oxide synthase activity in the human lower urinary tract and its correlation with neuroeffector responses. Urology. 1994;44:683–687. Abstract | Full-Text PDF (424 KB) | MEDLINE | CrossRef

[22]. [22]Korting GE, Smith SD, Wheeler MA, Weiss RM, Foster HE. A randomized double-blind trial of oral L-arginine for treatment of interstitial cystitis. J Urol. 1999;161:558–565. Abstract | Full Text | Full-Text PDF (926 KB) | MEDLINE | CrossRef

[23]. [23]Cartledge JJ, Davies AM, Eardley I. A randomized double-blind placebo-controlled crossover trial of the efficacy of L-arginine in the treatment of interstitial cystitis. BJU Int. 2000;85:421–426. MEDLINE | CrossRef

[24]. [24]Hurst RE, et al. A deficit of chondroitin sulfate proteoglycans on the bladder uroepithelium in interstitial cystitis. Urology. 1996;48:817–821. Abstract | Full-Text PDF (788 KB) | MEDLINE | CrossRef

[25]. [25]Parsons CL, Mulholland SG. Successful therapy of interstitial cystitis with pentosanpolysulfate. J Urol. 1987;138:513–516. MEDLINE

[26]. [26]Mulholland SG, Hanno P, Parsons CL, Sant GR, Staskin DR. Pentosan polysulfate sodium for therapy of interstitial cystitis. A double-blind placebo-controlled clinical study. Urology. 1990;35:552–558. Abstract | Full-Text PDF (1013 KB) | MEDLINE | CrossRef

[27]. [27]Parsons CL, Benson G, Childs SJ, Hanno P, Sant GR, Webster G. A quantitatively controlled method to study prospectively interstitial cystitis and demonstrate the efficacy of pentosanpolysulfate. J Urol. 1993;150:845–848. MEDLINE

[28]. [28]Nickel JC, et al. Randomized, double-blind, dose-ranging study of pentosan polysulfate sodium for interstitial cystitis. Urology. 2005;65:654–658. Abstract | Full Text | Full-Text PDF (98 KB) | CrossRef

[29]. [29]Holm-Bentzen M, et al. A prospective double-blind clinically controlled multicenter trial of sodium pentosanpolysulfate in the treatment of interstitial cystitis and related painful bladder disease. J Urol. 1987;138:503–507. MEDLINE

[30]. [30]Bumpus HR. Interstitial cystitis:its treatmentby overdistention of the bladder. Med Clin North Am. 1930;13:1495–1498.

[31]. [31]Gosling JA, Dixon JS, Dunn M. The structure of the rabbit urinary bladder after experimental distension. Invest Urol. 1977;14:386–389. MEDLINE

[32]. [32]Chai TC, Zhang CO, Shoenfelt JL, Johnson HW, Warren JW, Keay S. Bladder stretch alters urinary heparin-binding epidermal growth factor and antiproliferative factor in patients with interstitial cystitis. J Urol. 2000;163:1440–1444. Abstract | Full Text | Full-Text PDF (75 KB) | MEDLINE | CrossRef

[33]. [33]Rosamilia A, Cann L, Scurry J, Rogers P, Dwyer P. Bladder microvasculature and the effects of hydrodistention in interstitial cystitis. Urology. 2001;57:132. Abstract | Full Text | Full-Text PDF (251 KB) | CrossRef

[34]. [34]Dunn M, Ramsden PD, Roberts JB, Smith JC, Smith PJ. Interstitial cystitis, treated by prolonged bladder distension. Br J Urol. 1977;49:641–645. MEDLINE | CrossRef

[35]. [35]McCahy PJ, Styles RA. Prolonged bladder distension: experience in the treatment of detrusor overactivity and interstitial cystitis. Eur Urol. 1995;28:325–327. MEDLINE

[36]. [36]Glemain P, Riviere C, Lenormand L, Karam G, Bouchot O, Buzelin JM. Prolonged hydrodistention of the bladder for symptomatic treatment of interstitial cystitis: efficacy at 6 months and 1 year. Eur Urol. 2002;41:79–84. Abstract | Full Text | Full-Text PDF (178 KB) | MEDLINE | CrossRef

[37]. [37]Evans MS, Reid KH, Sharp JB. Dimethylsulfoxide (DMSO) blocks conduction in peripheral nerve C fibers: a possible mechanism of analgesia. Neurosci Lett. 1993;150:145–148. MEDLINE | CrossRef

[38]. [38]Sams WM. The effects of dimethyl sulfoxide on nerve conduction. Ann N Y Acad Sci. 1967;141:242–247. MEDLINE | CrossRef

[39]. [39]Barker SB, Matthews PN, Philip PF, Williams G. Prospective study of intravesical dimethyl sulphoxide in the treatment of chronic inflammatory bladder disease. Br J Urol. 1987;59:142–144. MEDLINE | CrossRef

[40]. [40]Fowler JE. Prospective study of intravesical dimethyl sulfoxide in treatment of suspected early interstitial cystitis. Urology. 1981;18:21–26. Abstract | Full-Text PDF (639 KB) | MEDLINE | CrossRef

[41]. [41]Theoharides TC, Sant GR. New agents for the medical treatment of interstitial cystitis. Expert Opin Investig Drugs. 2001;10:521–546. MEDLINE | CrossRef

[42]. [42]Sant GR. Intravesical 50% dimethyl sulfoxide (Rimso-50) in treatment of interstitial cystitis. Urology. 1987;29:17–21. Abstract | Full-Text PDF (489 KB) | MEDLINE

[43]. [43]Perez-Marrero R, Emerson LE, Feltis JT. A controlled study of dimethyl sulfoxide in interstitial cystitis. J Urol. 1988;140:36–39. MEDLINE

[44]. [44]Perez-Marrero R, Emerson LE, Maharajh DO, Juma S. Prolongation of response to DMSO by heparin maintenance. Urology. 1993;41:64–66. Abstract | Full-Text PDF (360 KB) | MEDLINE | CrossRef

[45]. [45]Hanno PM, Wein AJ. Medical treatment of interstitial cystitis (other than Rimso-50/Elmiron). Urology. 1987;29:22–26. MEDLINE

[46]. [46]Parsons CL, Housley T, Schmidt JD, Lebow D. Treatment of interstitial cystitis with intravesical heparin. Br J Urol. 1994;73:504–507. MEDLINE | CrossRef

[47]. [47]Kuo HC. Urodynamic results of intravesical heparin therapy for women with frequency urgency syndrome and interstitial cystitis. J Formos Med Assoc. 2001;100:309–314. MEDLINE

[48]. [48]Peters KM, Diokno AC, Steinert BW. Preliminary study on urinary cytokine levels in interstitial cystitis: does intravesical bacille Calmette-Guerin treat interstitial cystitis by altering the immune profile in the bladder?. Urology. 1999;54:450–453. Abstract | Full Text | Full-Text PDF (114 KB) | CrossRef

[49]. [49]Peters K, et al. The efficacy of intravesical Tice strain bacillus Calmette-Guerin in the treatment of interstitial cystitis: a double-blind, prospective, placebo controlled trial. J Urol. 1997;157:2090–2094. Abstract | Full Text | Full-Text PDF (584 KB) | MEDLINE | CrossRef

[50]. [50]Peters KM, Diokno AC, Steinert BW, Gonzalez JA. The efficacy of intravesical bacillus Calmette-Guerin in the treatment of interstitial cystitis: long-term followup. J Urol. 1998;159:1483–1486discussion 6–7. Abstract | Full Text | Full-Text PDF (556 KB) | MEDLINE | CrossRef

[51]. [51]Peeker R, Haghsheno MA, Holmang S, Fall M. Intravesical bacillus Calmette-Guerin and dimethyl sulfoxide for treatment of classic and nonulcer interstitial cystitis: a prospective, randomized double-blind study. J Urol. 2000;164:1912–1915discussion 5–6. Abstract | Full Text | Full-Text PDF (66 KB) | MEDLINE | CrossRef

[52]. [52]Mayer R, et al. A randomized controlled trial of intravesical bacillus calmette-guerin for treatment refractory interstitial cystitis. J Urol. 2005;173:1186–1191. Abstract | Full Text | Full-Text PDF (242 KB) | MEDLINE | CrossRef

[53]. [53]Buckley MS, Washington S, Laurent C, Erickson DR, Bhavananadan VP. Characterization and immunohistochemical localization of the glycoconjugates of the rabbit bladder mucosa. Arch Biochem Biophys. 1996;330:163–173. MEDLINE | CrossRef

[54]. [54]Hurst RE, Rhodes SW, Adamson PB, Parsons CL, Roy JB. Functional and structural characteristics of the glycosaminoglycans of the bladder luminal surface. J Urol. 1987;138:433–437. MEDLINE

[55]. [55]Erickson DR, Sheykhnazari M, Ordille S, Bhavanandan VP. Increased urinary hyaluronic acid and interstitial cystitis. J Urol. 1998;160:1282–1284. Abstract | Full Text | Full-Text PDF (395 KB) | MEDLINE | CrossRef

[56]. [56]Morales A, Emerson L, Nickel JC, Lundie M. Intravesical hyaluronic acid in the treatment of refractory interstitial cystitis. J Urol. 1996;156:45–48. Abstract | Full Text | Full-Text PDF (439 KB) | MEDLINE | CrossRef

[57]. [57]Porru D, et al. Results of treatment of refractory interstitial cystitis with intravesical hyaluronic acid. Urol Int. 1997;59:26–29. MEDLINE

[58]. [58]Nordling J, Jorgensen S, Kallestrup E. Cystistat for the treatment of interstitial cystitis: a 3-year follow-up study. Urology. 2001;57:123. Full Text | Full-Text PDF (65 KB) | CrossRef

[59]. [59]Kallestrup EB, Jorgensen SS, Nordling J, Hald T. Treatment of interstitial cystitis with Cystistat: a hyaluronic acid product. Scand J Urol Nephrol. 2005;39:143–147. MEDLINE | CrossRef

[60]. [60]Sant GR, LaRock DR. Standard intravesical therapies for interstitial cystitis. Urol Clin North Am. 1994;21:73–83. MEDLINE

[61]. [61]Messing EM, Freiha FS. Complication of Clorpactin WCS90 therapy for interstitial cystitis. Urology. 1979;13:389–392. Abstract | Full-Text PDF (591 KB) | MEDLINE | CrossRef

[62]. [62]Messing EM, Stamey TA. Interstitial cystitis: early diagnosis, pathology, and treatment. Urology. 1978;12:381–392. Abstract | Full-Text PDF (1548 KB) | MEDLINE | CrossRef

[63]. [63]Al-Hadithi HN, et al. Absence of bacterial and viral DNA in bladder biopsies from patients with interstitial cystitis/chronic pelvic pain syndrome. J Urol. 2005;174:151–154. Abstract | Full Text | Full-Text PDF (69 KB) | MEDLINE | CrossRef

[64]. [64]Lazzeri M, Spinelli M, Beneforti P, Malaguti S, Giardiello G, Turini D. Intravesical infusion of resiniferatoxin by a temporary in situ drug delivery system to treat interstitial cystitis: a pilot study. Eur Urol. 2004;45:98–102. Abstract | Full Text | Full-Text PDF (96 KB) | MEDLINE | CrossRef

[65]. [65]Payne CK, et al. Intravesical resiniferatoxin for the treatment of interstitial cystitis: a randomized, double-blind, placebo controlled trial. J Urol. 2005;173:1590–1594. Abstract | Full Text | Full-Text PDF (113 KB) | MEDLINE | CrossRef

[66]. [66]Chen TY, Corcos J, Camel M, Ponsot Y, Tu LM. Prospective, randomized, double-blind study of safety and tolerability of intravesical resiniferatoxin (RTX) in interstitial cystitis (IC). Int Urogynecol J Pelvic Floor Dysfunct. 2005;.

[67]. [67]Simpson LL. The origin, structure, and pharmacological activity of botulinum toxin. Pharmacol Rev. 1981;33:155–188. MEDLINE

[68]. [68]Cui M, Khanijou S, Rubino J, Aoki KR. Subcutaneous administration of botulinum toxin A reduces formalin-induced pain. Pain. 2004;107:125–133. Abstract | Full Text | Full-Text PDF (198 KB) | MEDLINE | CrossRef

[69]. [69]Schurch B, Schmid DM, Stohrer M. Treatment of neurogenic incontinence with botulinum toxin A. N Engl J Med. 2000;342:665. MEDLINE | CrossRef

[70]. [70]Smith CP, Radziszewski P, Borkowski A, Somogyi GT, Boone TB, Chancellor MB. Botulinum toxin a has antinociceptive effects in treating interstitial cystitis. Urology. 2004;64:871–875discussion 5. Abstract | Full Text | Full-Text PDF (222 KB) | CrossRef

[71]. [71]Hassouna MM, et al. Sacral neuromodulation in the treatment of urgency-frequency symptoms: a multicenter study on efficacy and safety. J Urol. 2000;163:1849–1854. Abstract | Full Text | Full-Text PDF (588 KB) | MEDLINE | CrossRef

[72]. [72]Shaker HS, Hassouna M. Sacral nerve root neuromodulation: an effective treatment for refractory urge incontinence. J Urol. 1998;159:1516–1519. Abstract | Full Text | Full-Text PDF (557 KB) | MEDLINE | CrossRef

[73]. [73]Leng WW, Chancellor MB. How sacral nerve stimulation neuromodulation works. Urol Clin North Am. 2005;32:11–18. Full Text | Full-Text PDF (256 KB) | MEDLINE | CrossRef

[74]. [74]Maher CF, Carey MP, Dwyer PL, Schluter PL. Percutaneous sacral nerve root neuromodulation for intractable interstitial cystitis. J Urol. 2001;165:884–886. Abstract | Full Text | Full-Text PDF (61 KB) | MEDLINE | CrossRef

[75]. [75]Comiter CV. Sacral neuromodulation for the symptomatic treatment of refractory interstitial cystitis: a prospective study. J Urol. 2003;169:1369–1373. Abstract | Full Text | Full-Text PDF (309 KB) | MEDLINE | CrossRef

[76]. [76]Peters KM, Carey JM, Konstandt DB. Sacral neuromodulation for the treatment of refractory interstitial cystitis: outcomes based on technique. Int Urogynecol J Pelvic Floor Dysfunct. 2003;14:223–228discussion 8. MEDLINE | CrossRef

[77]. [77]Peters KM, Konstandt D. Sacral neuromodulation decreases narcotic requirements in refractory interstitial cystitis. BJU Int. 2004;93:777–779. MEDLINE | CrossRef

[78]. [78]O’Reilly BA, et al. Transdermal posterior tibial nerve laser therapy is not effective in women with interstitial cystitis. J Urol. 2004;172:1880–1883. Abstract | Full Text | Full-Text PDF (71 KB) | MEDLINE | CrossRef

[79]. [79]Zhao J, Nordling J. Posterior tibial nerve stimulation in patients with intractable interstitial cystitis. BJU Int. 2004;94:101–104. MEDLINE | CrossRef

[80]. [80]Baykal K, Senkul T, Sen B, Karademir K, Adayener C, Erden D. Intravesical heparin and peripheral neuromodulation on interstitial cystitis. Urol Int. 2005;74:361–364. MEDLINE | CrossRef

[81]. [81]Hunner GL. A rare type ofbladder ulcer: further note, with a report of eigtheen cases. JAMA. 1918;70:203.

[82]. [82]Peeker R, Aldenborg F, Fall M. Complete transurethral resection of ulcers in classic interstitial cystitis. Int Urogynecol J Pelvic Floor Dysfunct. 2000;11:290–295. MEDLINE | CrossRef

[83]. [83]Shanberg AM, Baghdassarian R, Tansey LA. Treatment of interstitial cystitis with the neodymium-YAG laser. J Urol. 1985;134:885–888. MEDLINE

[84]. [84]Malloy TR, Shanberg AM. Laser therapy for interstitial cystitis. Urol Clin North Am. 1994;21:141–144. MEDLINE

[85]. [85]Rofeim O, Hom D, Freid RM, Moldwin RM. Use of the neodymium: YAG laser for interstitial cystitis: a prospective study. J Urol. 2001;166:134–136. Abstract | Full Text | Full-Text PDF (178 KB) | MEDLINE | CrossRef

[86]. [86]Hohenfellner M, Linn J, Hampel C, Thuroff J. Surgical treatment of interstitial cystitis in women. In: Sant GR editors. Interstitial cystitis. Philadelphia: Lippincott-Raven; 1997;p. 222.

[87]. [87]Lotenfoe RR, Christie J, Parsons A, Burkett P, Helal M, Lockhart JL. Absence of neuropathic pelvic pain and favorable psychological profile in the surgical selection of patients with disabling interstitial cystitis. J Urol. 1995;154:2039–2042. Abstract | Full Text | Full-Text PDF (413 KB) | MEDLINE | CrossRef

[88]. [88]Elzawahri A, et al. Urinary conduit formation using a retubularized bowel from continent urinary diversion or intestinal augmentations: ii. Does it have a role in patients with interstitial cystitis?. J Urol. 2004;171:1559–1562. Abstract | Full Text | Full-Text PDF (129 KB) | MEDLINE | CrossRef

[89]. [89]Chakravarti A, Ganta S, Somani B, Jones MA. Caecocystoplasty for intractable interstitial cystitis: long-term results. Eur Urol. 2004;46:114–117. Abstract | Full Text | Full-Text PDF (149 KB) | MEDLINE | CrossRef

[90]. [90]Nurse DE, Parry JR, Mundy AR. Problems in the surgical treatment of interstitial cystitis. Br J Urol. 1991;68:153–154. MEDLINE | CrossRef

[91]. [91]Peeker R, Aldenborg F, Fall M. The treatment of interstitial cystitis with supratrigonal cystectomy and ileocystoplasty: difference in outcome between classic and nonulcer disease. J Urol. 1998;159:1479–1482. Abstract | Full Text | Full-Text PDF (709 KB) | MEDLINE | CrossRef

[92]. [92]Propert KJ, Payne C, Kusek JW, Nyberg LM. Pitfalls in the design of clinical trials for interstitial cystitis. Urology. 2002;60:742–748. Full Text | Full-Text PDF (99 KB) | CrossRef

[93]. [93]Fleischmann JD, Huntley HN, Shingleton WB, Wentworth DB. Clinical and immunological response to nifedipine for the treatment of interstitial cystitis. J Urol. 1991;146:1235–1239. MEDLINE

[94]. [94]Kelly JD, Young MR, Johnston SR, Keane PF. Clinical response to an oral prostaglandin analogue in patients with interstitial cystitis. Eur Urol. 1998;34:53–56. MEDLINE | CrossRef

[95]. [95]Moran PA, Dwyer PL, Carey MP, Maher CF, Radford NJ. Oral methotrexate in the management of refractory interstitial cystitis. Aust N Z J Obstet Gynaecol. 1999;39:468–471. MEDLINE | CrossRef

[96]. [96]Bouchelouche K, Nordling J, Hald T, Bouchelouche P. The cysteinyl leukotriene D4 receptor antagonist montelukast for the treatment of interstitial cystitis. J Urol. 2001;166:1734–1737. Abstract | Full Text | Full-Text PDF (48 KB) | MEDLINE | CrossRef

[97]. [97]Soucy F, Gregoire M. Efficacy of prednisone for severe refractory ulcerative interstitial cystitis. J Urol. 2005;173:841–843discussion 3. Abstract | Full Text | Full-Text PDF (66 KB) | MEDLINE | CrossRef

[98]. [98]Forsell T, Ruutu M, Isoniemi H, Ahonen J, Alfthan O. Cyclosporine in severe interstitial cystitis. J Urol. 1996;155:1591–1593. Abstract | Full Text | Full-Text PDF (327 KB) | MEDLINE | CrossRef

[99]. [99]Sairanen J, Forsell T, Ruutu M. Long-term outcome of patients with interstitial cystitis treated with low dose cyclosporine A. J Urol. 2004;171:2138–2141. Abstract | Full Text | Full-Text PDF (79 KB) | MEDLINE | CrossRef

[100]. [100]van Ophoven A, Rossbach G, Oberpenning F, Hertle L. Hyperbaric oxygen for the treatment of interstitial cystitis: long-term results of a prospective pilot study. Eur Urol. 2004;46:108–113. Abstract | Full Text | Full-Text PDF (111 KB) | MEDLINE | CrossRef

[101]. [101]Theoharides TC, Sant GR. A pilot open label study of Cystoprotek in interstitial cystitis. Int J Immunopathol Pharmacol. 2005;18:183–188. MEDLINE

[102]. [102]Blaivas JG, Weiss JP, Desai P, Flisser AJ, Stember DS, Stahl PJ. Long-term followup of augmentation enterocystoplasty and continent diversion in patients with benign disease. J Urol. 2005;173:1631–1634. Abstract | Full Text | Full-Text PDF (65 KB) | MEDLINE | CrossRef

[103]. [103]van Ophoven A, Oberpenning F, Hertle L. Long-term results of trigone-preserving orthotopic substitution enterocystoplasty for interstitial cystitis. J Urol. 2002;167:603–607. Abstract | Full Text | Full-Text PDF (102 KB) | MEDLINE | CrossRef

[104]. [104]Costello AJ, Crowe H, Agarwal D. Supratrigonal cystectomy and ileocystoplasty in management of interstitial cystitis. Aust N Z J Surg. 2000;70:34–38. MEDLINE

[105]. [105]Linn JF, et al. Treatment of interstitial cystitis: comparison of subtrigonal and supratrigonal cystectomy combined with orthotopic bladder substitution. J Urol. 1998;159:774–778. Abstract | Full Text | Full-Text PDF (1123 KB) | MEDLINE | CrossRef

[106]. [106]Christmas TJ, Holmes SA, Hendry WF. Bladder replacement by ileocystoplasty: the final treatment for interstitial cystitis. Br J Urol. 1996;78:69–73. MEDLINE

[107]. [107]Smith GL, Christmas TJ. Interstitial ureteritis following cystectomy for interstitial cystitis. Br J Urol. 1996;77:607–608. MEDLINE

[108]. [108]Hughes OD, Kynaston HG, Jenkins BJ, Stephenson TP, Vaughton KC. Substitution cystoplasty for intractable interstitial cystitis. Br J Urol. 1995;76:172–174. MEDLINE | CrossRef

[109]. [109]Kontturi MJ, Hellstrom PA, Tammela TL, Lukkarinen OA. Colocystoplasty for the treatment of severe interstitial cystitis. Urol Int. 1991;46:50–54. MEDLINE

[110]. [110]Nielsen KK, Kromann-Andersen B, Steven K, Hald T. Failure of combined supratrigonal cystectomy and Mainz ileocecocystoplasty in intractable interstitial cystitis: is histology and mast cell count a reliable predictor for the outcome of surgery?. J Urol. 1990;144:255–258discussion 8–9. MEDLINE

[111]. [111]Webster GD, Maggio MI. The management of chronic interstitial cystitis by substitution cystoplasty. J Urol. 1989;141:287–291. MEDLINE

[112]. [112]Freiha FS, Faysal MH, Stamey TA. The surgical treatment of intractable interstitial cystitis. J Urol. 1980;123:632–634. MEDLINE

[113]. [113]Wammack R, Remzi M, Seitz C, Djavan B, Marberger M. Efficacy of oral doxepin and piroxicam treatment for interstitial cystitis. Eur Urol. 2002;41:596–600discussion 1. Abstract | Full Text | Full-Text PDF (96 KB) | MEDLINE | CrossRef

[114]. [114]Ghoniem GM, McBride D, Sood OP, Lewis V. Clinical experience with multiagent intravesical therapy in interstitial cystitis patients unresponsive to single-agent therapy. World J Urol. 1993;11:178–182. MEDLINE

[115]. [115]Bade JJ, Peeters JM, Mensink HJ. Is the diet of patients with interstitial cystitis related to their disease?. Eur Urol. 1997;32:179–183. MEDLINE

Department of Urology, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, Montreal, QC, Canada

Corresponding author. Department of Urology, Sir Mortimer B. Davis-Jewish General Hospital, room E-210, 3755 Côte St. Catherine Road, Montreal, Canada QC H3T 1E2. Tel. +1 514 340 8222#5166; Fax +1 514 340 7559.

PII: S1871-2592(05)00058-4

doi:10.1016/j.eeus.2005.10.001

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