Medical treatments for painful bladder syndrome (interstitial cystitis)
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
To compare the effectiveness of oral medication with placebo and other treatments for painful bladder syndrome (interstitial cystitis) in adults.
The hypotheses to be tested are as follows:
1. Oral treatment is better than placebo or no treatment.
2. One oral treatment is better than another oral treatment.
3. Oral treatment is better than other methods of delivering pharmacological treatment.
4. Oral treatment is better than other modes of treatment eg. dietary and lifestyle changes.
5. Oral treatment combined with any other form of treatment is better than the other treatment alone.
Background
The condition
Painful bladder syndrome (interstitial cystitis) is a chronic condition seen mainly in women (10:1 female to male ratio) and characterised by pain, urgency, frequency and nocturia. There are cystoscopic and histological features which are said to be typical and these are the basis of a diagnosis of 'interstitial cystitis'. However, in many cases the diagnosis is one of the exclusion having ruled out specific causes such as infection and malignancy; this has led to the broader, less specific label of 'painful bladder syndrome'. Overactive Bladder (OAB) shows some similarity in its clinical presentation but without the pain, which is the defining symptom of painful bladder syndrome (interstitial cystitis).
The prevalence of painful bladder syndrome (interstitial cystitis) varies between populations and ranges from 8 out of 100,000 in the Netherlands to 500 out of 100,000 in some parts of the USA (Nickel 2002). In part, this is due to a lack of standardised diagnostic criteria and a wide variation in the investigative steps undertaken to make the diagnosis. The strictest diagnostic criteria are those used by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) in their research definition of interstitial cystitis (Gillenwater 1988). This requires both cystoscopy and cystometry to exclude other possible causes for patient symptoms and also describes minimum criteria for age, duration of symptoms, degree of frequency and nocturia. These criteria have allowed a reasonably homogeneous group of patients to be identified for research purposes but there is controversy as to their usefulness for routine clinical diagnosis. A particular finding at cystoscopy is that of Hunner's ulceration which, if present, is an inclusion NIDDK criteria. Distinction has been made between ulcerative and non‐ulcerative variants of the condition in terms of pathophysiology and prognosis (Payne 2003).
The underlying pathophysiology of painful bladder syndrome (interstitial cystitis) is incompletely understood and the condition is increasingly viewed as being multifactorial (Nickel 2002). A loss of integrity at the epithelial surface of the bladder, possibly due to an infective or other inflammatory insult, is thought to be important along with sensory nerve up‐regulation and enhanced mast cell activation (Sant 2002). The end result of this process is a form of regional neuropathy that can have other gynaecological and gastrointestinal manifestations as well as pain and voiding symptoms (Nickel 2002). The clinical course of painful bladder syndrome and the prevalence of antinuclear antibodies in some cases has given rise to an autoimmune theory of pathophysiology.
The intervention
The multiple theories of pathogenesis proposed have resulted in the development of a large range of treatments. These have included oral medication, intravesical or bladder instillation therapy, dietary changes, lifestyle interventions, peripheral or transcutaneous nerve stimulation, and surgical intervention. Combinations of different treatment methods have been used aiming to enhance beneficial effects. This review will focus on those treatments where medication is administered orally. A systematic review of intravesical treatment for painful bladder syndrome (interstitial cystitis) is currently in progress (Dawson 2006).
Oral treatments for IC are listed below, along with the putative mode of action.
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Pentosan polysulfate ‐ reduces the permeability of the bladder mucosa to toxic urine components and inhibits histamine release from connective tissue and mucosal mast cells.
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Hydroxyzine ‐inhibits mast‐cell degranulation and has muscle relaxant, antihistamine, anticholinergic, and analgesic effects.
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Benzydamine ‐ non‐steroidal anti‐inflammatory.
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Steroids ‐ anti‐inflammatory effect.
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Cimetidine ‐ histamine H2‐receptor antagonist.
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Oxybutinin ‐ anticholinergic effect to reduce bladder spasm.
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Amitriptyline and other tricyclic antidepressants ‐ anticholinergic, analgesic and possible antihistamine effects.
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Rifampin ‐ antibiotic.
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Antibiotic regimens, eg sequence of doxycycline, erythromycin, metronidazole, clindamycin, amoxicillin and ciprofloxacin.
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L‐arginine ‐nitric oxide pathway, effect should be to relax smooth muscle and decrease pain; may also have immunological effects.
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Recombinant human nerve growth factor.
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Flavoxate ‐anti‐spasmodic agent.
If other oral preparations/medicines which are not listed here are identified during the review they will also be assessed, provided that the trial inclusion criteria are met.
Objectives
To compare the effectiveness of oral medication with placebo and other treatments for painful bladder syndrome (interstitial cystitis) in adults.
The hypotheses to be tested are as follows:
1. Oral treatment is better than placebo or no treatment.
2. One oral treatment is better than another oral treatment.
3. Oral treatment is better than other methods of delivering pharmacological treatment.
4. Oral treatment is better than other modes of treatment eg. dietary and lifestyle changes.
5. Oral treatment combined with any other form of treatment is better than the other treatment alone.
Methods
Criteria for considering studies for this review
Types of studies
Randomised or quasi randomised trials. Cross‐over trials will also be included if they randomly allocate participants to order of intervention.
Types of participants
Much research has been focused on a relatively homogenous group of subjects who meet the NIDDK criteria. In practice the diagnosis and subsequent treatment of the condition is often based on less rigid clinical grounds. Studies will be therefore considered for this review if they comprise adults in whom a clinical diagnosis of painful bladder syndrome (interstitial cystitis) has been made, with or without meeting NIDDK criteria.
Types of interventions
A trial where at least one of the arms is oral treatment. The exact drug or preparation being administered by this route is not pre‐specified and there may be a range of possibilities as described in the protocol background above.
Comparison may be with either:
1) Placebo or no treatment;
2) Another preparation, or combination of preparations, administered orally;
3) Any other treatment, including one administered by the intravesical route; or
4) Non‐oral treatment, such as dietary or lifestyle measures.
Types of outcome measures
The primary outcome measures are pain, bladder capacity and voiding frequency. Pain assessment is subjective and relies on patient self‐reporting. It may involve the use of specific pain scores or scales as well as descriptive endpoints. Bladder capacity and frequency may be assessed either from patient bladder diaries (which should include measured void volumes) or from urodynamic investigations.
Secondary outcome measures will include patient‐reported outcomes such as voiding frequency, episodes of nocturia or nocturnal enuresis; objective cystoscopic and histological findings.
Quality of Life information, both general and condition‐specific with data from appropriate questionnaires will be sought. In the case of condition‐specific measures we will analyse and present results separately for different measures, eg O'Leary Sant (O’Leary 1997), Wisconsin (Goin 1998), PUF (Parsons 2002).
Economic outcomes: are measures of direct and indirect costs of treatment, and formal economic analyses of treatment.
Other outcomes are: adverse events/side effects; any long‐term follow‐up data; need for further treatment; other outcomes not pre‐specified but judged important when carrying out review.
Search methods for identification of studies
This review will draw on the search strategy developed for the Incontinence Group as a whole. Relevant trials will be primarily identified from the Cochrane Incontinence Group trials register. The methods used to derive this, including the search strategy, are described under the Group's details in The Cochrane Library (For more details please see the ‘Specialized Register’ section of the Group’s module in The Cochrane Library). The register contains trials identified from MEDLINE, CINAHL and the Cochrane Central Register of Controlled Trials (CENTRAL) and hand searching of journals and conference proceedings. Additionally all reference lists of selected trials will also be searched. No limitations will be placed on the searches.
Data collection and analysis
Identified trials will be selected for inclusion in the review on the basis of appropriateness as determined by two independent reviewers without prior consideration of the results. Non‐English language publications will be translated. The reviewers will independently assess the methodological quality of the trials using the Incontinence Group's quality assessment criteria including quality of randomisation and allocation concealment, description of withdrawal and dropout, and intention to treat analysis. Any disagreements will be resolved by discussion and if necessary referred to the editorial team.
For each eligible study, data relevant to the characteristics of study, participants interventions and pre‐stated outcome measures, and participants will be independently abstracted by two review authors. An attempt will be made to contact authors to acquire any missing or unreported study data. In the event of duplicate publications, the studies will be treated as a single source of data.
As a general rule, results will be presented for unfavourable events and, where appropriate, data will be combined quantitatively. Binary outcomes will be presented as relative risk, and continuous outcomes by mean differences, accompanied by 95% confidence intervals . If different tools are used to measure outcomes such as quality of life, standardised mean differences will be considered. Cross‐over trials will be analysed using the generic inverse variance method where possible. Synthesis will be done using a fixed effects model in the first instance. The I squared statistic (Higgins 2002; Higgins 2003) in conjunction with the chi‐squared test for heterogeneity and visual inspection of the forest plots will be used to assess heterogeneity. Where heterogeneity exists the characteristics of the studies will be examined to look for potential causes. If none are found, further analysis with a random effects model and the use of sensitivity analyses will be undertaken. If meta‐analysis is inappropriate then a descriptive comparison will be made instead.
If justified by the number of eligible trials and their participant inclusion criteria, subgroup analyses will be performed on those trials where inclusion was based on NIDDK criteria and where data are available on patients with and without Hunner's ulcers.
