What is the most effective treatment of interstitial cystitis?BMJ 2008; 337 doi: https://doi.org/10.1136/bmj.a2325 (Published 27 November 2008) Cite this as: BMJ 2008;337:a2325
- Joseph L Onwude, consultant gynaecologist and medical statistician
- Correspondence to: J L Onwude, Community Gynaecology Ltd, Chelmsford CM1 3RW
- Accepted 2 April 2008
The treatment of interstitial cystitis has many uncertainties, including which treatment is the most effective. Interstitial cystitis is a chronic inflammatory bladder disease that mostly affects women. It can present as recurrent non-bacterial cystitis or as chronic pelvic pain associated with frequency and urgency. It can take up to five years and five doctors to reach the correct diagnosis.w1 Patients with interstitial cystitis are not a homogeneous population. Two distinct types of disease—classic and non-ulcer interstitial cystitis—have been described on the basis of pathological findings, and some treatments might work better for one type than for the other.1 Currently no treatment ladder exists. Oral treatments should be first line and intravesical therapies second line.
Interstitial cystitis can be a debilitating disease and has been described in the United States as a major health problem.w2 The prevalence ranges from 5 per 100 000 women in Japan to 197 per 100 000 women and 41 per 100 000 men in the US.w3 w4 We have no prevalence estimates for the United Kingdom.
Because interstitial cystitis is a distinct pathologic entity, a biopsy can provide definitive diagnosis.w5 However, criteria from the US National Institute of Diabetes and Digestive and Kidney Diseases, which required cystoscopy and bladder distension, need no longer be used.w6 Instead, validated questionnaires like the O’Leary-Sant symptom index and the University of Wisconsin symptom index are now used to diagnose this condition and measure response to treatment.w7
In addition, the International Continence Society now recommends the term interstitial cystitis/painful bladder syndrome to describe all cases of urinary pain that cannot be attributed to other causes, such as infection or urinary stones. Interstitial cystitis is used alone when describing cases that meet criteria of the US National Institute of Diabetes and Digestive and Kidney Diseases.
Patients with interstitial cystitis vary greatly in type and severity of symptoms, and the symptoms overlap with those of painful bladder syndrome and many other clinical entities. A recent systematic review of symptoms showed that interstitial cystitis and painful bladder syndrome share a similar cluster of symptoms, such as pelvic and bladder pain, urinary frequency, urgency, and nocturia.w8 Hence a bladder biopsy is needed to confirm interstitial cystitis when a case of interstitial cystitis/painful bladder syndrome has been distinguished from recurrent urinary tract infections (by urine culture), overactive bladder, vulvodynia, chronic urethral syndrome, and endometriosis.
What is the evidence of uncertainty?
Interstitial cystitis currently has no standard treatment. One large study recorded 183 different treatments, and just under half of the women received a combination of two or more treatments.w9
Randomised studies of drugs used for this condition have produced conflicting results. For example, a recent study of oral pentosan polysulfate sodium (Elmiron), a mucosal surface protectant, found that global improvement was similar to that for placebo after 24 weeks’ treatment,2 whereas a meta-analysis of four earlier studies showed that it was superior to placebo in relief of pain, urgency, and frequency, but not nocturia, after 12 weeks’ treatment.3 One study of 300 mg, 600 mg, and 900 mg of pentosan polysulfate sodium showed no difference in clinical response after 32 weeks of treatment.w10 In another study, oral ciclosporin A, an immunosuppressant, was superior to oral pentosan polysulfate sodium in global symptom response after 24 weeks’ treatment.4 Uncertainty therefore exists regarding this commonly used oral treatment.
Results for oral L-arginine, a substrate for nitric oxide synthesase, are also conflicting. One study showed superior global improvement after 12 weeks compared with placebo,5 whereas another showed no superiority over placebo.6 Similarly, one study of intravesical BCG showed benefit7 and another showed no superiority over placebo.8
Amitriptyline, a tricyclic antidepressant, improved symptom scores more than placebo after 16 weeks’ treatment, although anticholinergic side effects were significantly worse.9
Current randomised evidence on intravesical resiniferatoxin,10 a vanilloid receptor agonist which desensitises C fibres that transmit pain; intravesical pentosan polysulfate sodium11; and sequential oral antibiotics12 show no significant benefit over placebo in global symptom response after three months’ treatment.
No randomised studies exist for oral cimetidine in interstitial cystitis, although it has been shown to be superior to placebo in patients with painful bladder disease.13
Bladder irrigation with dimethyl sulfoxide, an anti-inflammatory analgesic, was superior to placebo in subjective and objective measures after eight weeks’ treatment.14 This drug was also superior to intravesical BCG in a head to head drug trial.1 However, treatment with dimethyl sulfoxide is still uncertain. The evidence of benefit comes from two small trials of 53 subjects with a mean age of 48 years and a mean duration of symptoms of 5.5 years. These benefits cannot be generalised to all patients without larger trials or systematic reviews.
As a result of these uncertainties, the range of treatments offered to patients differs worldwide. For example, in the US, oral pentosan polysulfate sodium is used extensively, whereas dimethyl sulfoxide is more widely used in the Netherlands.w11 In the UK, the range of treatments is wide but drugs of “proven” efficacy were given to fewer than a third of patients.w12
Is ongoing research likely to provide relevant evidence?
A phase III study of the efficacy and safety of amitriptyline in painful bladder syndrome is still recruiting in North America.15 The balance between benefits and adverse effects after 26 weeks’ treatment should become clearer. Another randomised study is evaluating the effectiveness of acupuncture in alleviating symptoms of interstitial cystitis/painful bladder syndrome, between 12 and 24 weeks of treatment.w13
Although a Cochrane protocol for intravesical treatment of interstitial cystitis is available,w14 a separate systematic review of oral treatments is needed. This should examine the evidence of efficacy of oral treatments versus placebo, one oral treatment against another, oral treatment versus other modes of treatment such as dietary and lifestyle changes, and oral treatment combined with another form of treatment versus the other treatment alone.
What should we do in the light of the uncertainty?
Patients and clinicians should understand the limitations of the evidence for current treatments and set realistic treatment goals. Before a diagnosis of interstitial cystitis is made, patients who report that their symptoms are triggered or exacerbated by certain foods or drinks might be advised to avoid them, although the evidence for avoidance was weakened by reporting bias.w15 Oral or intravesical treatments that produce modest benefit in some patients should be considered in sequence or combination, because no single treatment is likely to improve interstitial cystitis in all patients.
With this level of uncertainty, and until further evidence becomes available, a clinician faced with a patient with interstitial cystitis should consider offering six doses of intravesical dimethyl sulfoxide over three months. Apart from the transient garlic smell in some patients, and a report of eosinophilic cystitis,w16 the safety of dimethyl sulfoxide is established, and it is an effective early treatment for interstitial cystitis.w17-w19
Recommendation for further research
A randomised controlled study of intravesical dimethyl sulfoxide, pentosan polysulfate (or Gepan instill), and placebo in women with biopsy confirmed interstitial cystitis
Population: women with biopsy confirmed interstitial cystitis
Intervention: six courses of intravesical dimethyl sulfoxide, intravesical pentosan polysulfate or Gepan instill and intravesical placebo
Comparison: symptom scores on the O’Leary-Sant symptom index or the University of Wisconsin symptom index
Outcome: improvement in global scores for the three drugs compared with placebo
Cite this as: BMJ 2008;337:a2325
This is a series of occasional articles that highlights areas of practice where management lacks convincing supporting evidence. The series advisers are David Tovey, editorial director, BMJ Knowledge, and Charles Young, editor of BMJ Clinical Evidence, and editor in chief, BMJ Point of Care.
Competing interests: None declared.
Provenance and peer review: Not commissioned; externally peer reviewed.