R. Thilagarajah, Department of Urology, St. George's Healthcare NHS Trust, Blackshaw Road, London, SW17 0QT.
Objective To evaluate the efficacy of oral cimetidine as a treatment for painful bladder disease (PBD, variously described as a ‘symptom complex’ of suprapubic pain, frequency, dysuria and nocturia in the absence of overt urine infection) by assessing symptom relief and histological changes in the bladder wall tissue components, compared with placebo.
Patients and methods The study comprised 36 patients with PBD enrolled into a double-blind clinical study with two treatment arms, i.e. oral cimetidine or placebo, for a 3-month trial. Patients were asked to complete a symptom questionnaire (maximum score 35), and underwent cystoscopy and bladder biopsy before treatment allocation. On completing treatment the patients were re-evaluated by the questionnaire and biopsy. The symptom scores and bladder mucosal histology were compared before and after treatment, and the results analysed statistically to assess the efficacy of cimetidine.
Results Of the 36 patients recruited, 34 (94%) completed the study. Those receiving cimetidine had a significant improvement in symptoms, with median symptom scores decreasing from 19 to 11 (P < 0.001). Suprapubic pain and nocturia decreased markedly (P = 0.009 and 0.006, respectively). However, histologically the bladder mucosa showed no qualitative change in the glycosaminoglycan layer or basement membrane, or in muscle collagen deposition, in either group. The T cell infiltrate was marginally decreased in the cimetidine group (median 203 before and 193 after) and increased in the placebo group (median 243 and 250, P > 0.3 and > 0.2, respectively). Angiogenesis remained relatively unchanged. The incidence of mast cells and B cells was sporadic in both groups.
Conclusions Oral cimetidine is very effective in relieving symptoms in patients with PBD but there is no apparent histological change in the bladder mucosa after treatment; the mechanism of symptom relief remains to be elucidated.
Painful bladder disease (PBD) encompasses a spectrum of conditions that include a symptom complex of suprapubic pain, frequency, dysuria and nocturia in the absence of detectable urine infection. Ulcerative and nonulcerative IC, painful bladder syndrome (PBS), abacterial cystitis and the urethral syndrome are all contained within this wide-ranging term, as defined by international guidelines . Previously, we have used the term PBS to describe this entity (which does not progress to fulminating IC) [2,3], but in keeping with the guidelines we have adopted PBD to define this patient group.
In bladder mucosal biopsies a consistent feature of PBD is a T cell-rich chronic inflammatory infiltrate in the lamina propria, with submucosal angiogenesis and collagen deposition in the muscularis . Mast cell degranulation within the bladder wall has been implicated as a possible initiating factor in this inflammatory process and it is believed to be as a result of histamine release from these cells [4–7].
Whilst cimetidine was developed in the 1970s as an orally active, competitive H2-receptor antagonist for treating peptic ulcer disease [8,9], in 1987 Meares  used oral cimetidine for treating IC, on a purely speculative basis, with a reported improvement in symptoms. A subsequent study by Seshradi et al. supported this finding, with overall symptomatic relief in 66% of patients with IC. Similarly, Lewi  showed a 71% improvement in symptoms and complete cessation of pain in 45% of patients with biopsy-proven IC. As our patients had a chronic inflammatory response akin to nonulcerative IC, we tested the efficacy of cimetidine as a treatment for PBD. To date, no randomized controlled trials have been conducted to determine the efficacy of oral cimetidine in bladder disease. In the present study, we assessed any improvement in symptom scores and any histological changes in bladder biopsies before and after treatment, to determine the efficacy of cimetidine compared with placebo.
Patients and methods
Thirty-six patients (35 women, mean age 42 years, range 23–73) with a diagnosis of PBD were entered into a prospective, randomized, double-blind study with two treatment arms, placebo or cimetidine. Ethical approval for the study was obtained from St Mary's Hospital NHS Trust Ethical Committee. The diagnosis of PBD was based on the following criteria: (i) a clinical history of suprapubic pain, frequency and occasionally urgency, nocturia and dysuria, lasting for < 3 months despite repeatedly negative urine culture; (ii) petechial haemorrhages apparent on cystoscopy after distension; (iii) a histological examination of bladder biopsies taken from the patients, which showed a chronic inflammatory infiltrate with submucosal angiogenesis and increased collagen deposition in the muscle. The basement membrane also appeared discontinuous; (iv) urodynamic studies were deemed unnecessary for a diagnosis of PBD as, in keeping with previous studies, results obtained in this group of patients are too variable to be valid .
Patients were excluded from the study: if they had taken antibiotics, NSAIDs or had undergone intravesical therapy in the preceding month; in women, if there was any possibility of pregnancy, as there is a theoretical risk of teratogenic effects in the fetus under H2-antagonist treatment ; if there was a history of renal/hepatic impairment or blood dyscrasias, as these may worsen or become apparent during treatment with cimetidine ; if there was concomitant treatment with drugs metabolized within the liver using the P450 cytochrome family of enzymes (warfarin, phenytoin, quinidine, theophylline and tricyclic antidepressants), as cimetidine can inhibit these enzymes .
At the first consultation after initial cystoscopy and biopsy, patients were asked to complete a validated questionnaire detailing their medical history, previous medical and surgical treatments, diet history and urinary symptoms. Symptoms of frequency, urgency, suprapubic pain, nocturia and dysuria were scored from 0 to 5 according to severity (see Appendix 1). Each patient was then blindly allocated to receive either oral cimetidine 400 mg or placebo (both twice daily). After 3 months of treatment patients were invited for a repeat cystoscopy with biopsy, and a reassessment of their symptoms using the urinary symptom questionnaire.
The bladder biopsies were fixed in formalin and routinely processed to paraffin wax. Sections were cut at 3 µm and stained with haematoxylin and eosin, Gimenez, toluidine blue, elastin van Gieson, periodic acid-Schiff and Alcian blue. Sections were also immunostained using standard techniques with Q-BEND 10, UCHL1 and MB2 polyclonal antibodies. Using a microscope-mounted digital camera (Olympus DP10, Hamburg, Germany), an image of each slide (at × 260) was stored digitally. Each image was then viewed on a computer monitor with a 100-square counting grid generated over each image, to enable chronic inflammatory cells, T cells, B cells, macrophages, fibroblasts and mast cells in the lamina propria of the specimens to be counted. For each count, the image grid was positioned randomly over the tissue and only those cells within complete grid squares were included. The random positioning was obtained by removing the grid overlay, repositioning the image to include a nonconsecutive field and then generating the grid once more. This was repeated five times for each specimen, ensuring that fields were not consecutive. To assess submucosal blood vessel concentration, the generated grid was randomly placed over the image parallel to the mucosal surface and the number of blood vessels in a field comprising 1 × 10 grid squares was counted (Fig. 1). This was repeated five times for each specimen, to give a representative count as before. Finally, the specimens were assessed visually for a continuous or discontinuous basement membrane and an increase or decrease of collagen deposition in the underlying detrusor muscle.
At the end of the study the allocation of groups was revealed and the results analysed statistically using the paired t-test and Mann-Whitney U-test to ascertain whether there were any significant changes in individual and overall symptom scores, and in histological change in the bladder biopsies, between patients in the treatment and placebo arms of the study. Differences were considered significant at P < 0.05.
Of the 36 patients recruited, 34 (94%; 33 women, median age 42 years, range 23–73) completed the study; of the two patients lost to follow-up, one was from each group. The median (range) duration of disease was 4 (1–12) years. The patients were assessed in terms of age, ethnic group, diet history and pretreatment symptom score, to exclude differences in entry characteristics.
The results from the questionnaires before and after treatment showed a significant improvement in symptoms in those patients taking cimetidine compared with placebo (Table 1). The median total symptom scores decreased from 19.7 to 11.9 in the treated group, compared with 19.4 to 18.7 in the placebo group (P < 0.05). Significant relief in the cimetidine group was evident in the symptom scores of suprapubic pain (3.4 to 1.5) and nocturia (3.3 to 1.3; P = 0.009 and 0.006, respectively). The median (range) bladder capacity measured under anaesthesia was 770 (230–1105) mL.
Histological examination of the bladder biopsy specimens before and after treatment showed no significant qualitative change in the glycosaminoglycan (GAG) layer, basement membrane layer or collagen deposition in muscle within the groups. The histological quantification of bladder wall biopsy components is shown in Table 1. The overall assessment of the histological composition of cells/tissue components showed no statistical difference between the two groups of patients, before or after treatment.
Painful bladder disease is a complex entity, and has been a source of confusion and misery for both patients and clinicians for over a century. Early work by Skene  in the 1880s and later Hunner in 1914  established IC as a separate disease process. In 1951, Bourque proposed the current concept of the painful bladder . Research into the aetiology and pathogenesis of this condition has continued, but two major impediments remained: both researchers and clinical urologists could not agree on the exact criteria necessary for diagnosing this condition; and second, the nomenclature was vague, with terms being used interchangeably for the same process and with no international agreement. The situation was clarified to a degree in 1987, when guidelines for diagnosing IC were described . Some have suggested that PBS exists as a separate entity within the spectrum of PBD [2,3,19]. Messing and Stamey  proposed the idea of a ‘nonulcerative’ form of IC, which is similar if not the same as PBS. We propose that the term PBS should be abandoned completely in favour of nonulcerative IC. There appears to be no real evidence that the two differ and again it simplifies the nomenclature for everyday use. PBD should remain the term for this family of conditions, with two subdivisions; ulcerative (‘classical’) IC and nonulcerative IC. The present study refers to PBD rather than IC, specifically in the need for or omission of urodynamics in assessing these patients. The published guidelines are clear about the inclusion of urodynamic findings as part of the criteria for diagnosing IC , but some authors have disputed the relevance of this test in the diagnosis. The development of pain during the early filling phase of urodynamics usually brings the study to a premature end and hence precludes any useful information being obtained about bladder capacity [4,21]. Thus urodynamics were not routinely used in the present patients; bladder capacity was measured under general anaesthetic so that an objective measure of true bladder capacity could be obtained. This method has been supported by previous work [22,23]. The term PBD was used in this work, as opposed to IC, to avoid the problem of an exact definition; the debate on nomenclature will no doubt continue.
The pathogenesis of PBD remains unknown and various hypotheses have been proposed. Histological changes accompanying this diagnosis have included increased mast cell counts [23–25], structural changes in the GAG layer [26–28], nerve growth  and submucosal angiogenesis . We showed previously that the chronic inflammatory infiltrate seen in PBD consists mainly of T lymphocytes, when compared with normal controls. B cells were almost absent, indicating that the process was more likely to be cell-mediated rather than humoral . Harrington et al. also showed an increase in T cell infiltrate in ‘nonulcer’ IC. This predominance of T cells gives credence to the hypothesis that PBD may be an autoimmune phenomenon .
An alternative explanation is that activation of the inflammatory cascade via cytokines interleukin-1 and -6 and TNF instigate the T cell response. Bacterial lipopolysaccharide can induce these inflammatory components [32,33], thereby initiating the cascade response. This hypothesis is attractive as it may explain why no infective agent is present at the time of diagnosis. Once the inflammatory response is induced, the chronic inflammatory process becomes self-perpetuating by the activation and re-activation of other components, e.g. mast cells, histaminergic nerve fibres and the T cells already present.
The placebo effect is marked and therefore the statistical analysis of the results of any study will be hampered [23,34]. The present study assumed a placebo effect of up to 30% and symptomatic improvement with oral cimetidine of 70% [12,23]. Perez-Marrero et al. examined the responses of patients with IC using intravesical DMSO vs placebo; they reported a marked improvement in the DMSO group of 40%, compared with 18% in the placebo group. Messing and Stamey  reported a 72% success rate in 38 patients receiving intravesical chlorpactin WCS-90, but this treatment had to be administered under general anaesthesia and there was one case of vesico-urethral fibrosis in the series. The size of the present study was justified as; (i) a true significant statistical difference was not considered to be as important as a measurable clinical difference in the assessment of symptomatic relief; and (ii) the rarity of this condition would preclude enrolling sufficient patients for a larger study.
The clinical improvement in suprapubic pain and nocturia in patients taking cimetidine was statistically significant. There was also an overall improvement in total well-being after 3 months of treatment; the efficacy of oral cimetidine was therefore confirmed. The implications for our practice are two-fold: the standard treatment used at our hospital before this study consisted of a 6-week course of weekly intravesical therapy using a mixture of DMSO, sodium hydrogen carbonate, polyanion and hydrocortisone. The cost of this treatment was £214 for a full course, and necessitates hospital visits; a 3-month course of cimetidine costs £22. Cimetidine is a safe, oral therapy, available with no prescription, is well tolerated by most patients and provides good symptom relief. Oral administration was desirable for patients rather than intravesical therapy, enabling cimetidine to be used as an initial therapy, with intravesical therapy reserved for resistant cases.
The initial hypothesis was that cimetidine was bound to histamine H2 receptors on mast cells, hence blocking the release of histamine, which would then inhibit an inflammatory response. From the present results it appears that either mast cell action has a lesser role in the presentation and propagation of this condition, or the mast cell initiating step occurs long before diagnosis and before any treatment has been instigated. That there were no significant histological changes associated with cimetidine treatment was surprising. There was no evidence from this study that cimetidine had any obvious effect on the inflammatory infiltrate.
Mavligit  described the immunomodulatory effects of cimetidine and its potential uses. Melmon et al. reported that suppressor T cells expressed H2-receptor sites on their surface and further work showed that histamine played a pivotal role as a suppressor of cellular immune function [35,37]. Cimetidine has both an immune-modulating and immune-enhancing effect, by its ability to block the H2-receptor of the suppressor T cell [38,39]. Cimetidine may have an immune-modulating effect on the bladder mucosa of patients with PBD, suppressing the suppressor T cells. This would enhance the immune response by blocking the histamine effect on these cells, and might account for the histological findings (i.e. minimal quantitative changes) in the present patients after treatment. Chronic inflammation takes a long time to resolve and this may explain why this infiltrate was still present. Also, cimetidine is a symptomatic treatment but does not cure the underlying disease. Symptoms tended to recur in some patients once treatment with cimetidine ceased.
In conclusion, cimetidine is a safe, orally active, inexpensive alternative to intravesical therapy for the relief of symptoms of PBD. We suggest that cimetidine may have an immune-modulating effect on T cells within the inflammatory infiltrate, rather than stabilizing mast cells. Further research is needed to elucidate the effect of cimetidine on the T cell subsets in the bladder mucosa of patients with PBD.
R. Thilagarajah, FRCS, Specialist Registrar in Urology.
R.O'N. Witherow, MS, FRCS, Consultant Urologist.
M.M. Walker, FRCPath, Senior Lecturer and Honorary Consultant, Histopathology.
The patient questionnaire
History of urinary symptoms
How long have you had your present urinary symptoms? ______ years ______ months
Are the symptoms
If intermittent, what is the interval between attacks? ____
Please list the:
Aggravating factors Relieving factors
Questions 1–6 are scored as:
0 – Never
1 – Occasionally
2 – Less than half the time
3 – Half the time
4 – More than half the time
5 – All of the time
1. How often do you need to pass urine within 2 h of urinating?
2. How often do you feel that you need to pass urine and cannot wait?
3. How often do you get pain or burning on passing urine?
4. Do you get the feeling of incomplete emptying after finishing passing urine?
5. How often to you get lower abdominal pain associated with the symptoms?
6. Does passing urine relieve the pain?
7. Do you have to pass urine at night after going to bed?
0 – Never
1 – Once
2 – Twice
3 – Three times
4 – Four times
5 – Five times or more
Table 1. Symptom scores and the histological assessment of bladder biopsy specimens in patients with PBD before and after treatment with cimetidine or placebo (17 in each group). B cells and mast cells were negligible in both groups before and after treatment