Overview for healthcare professionals

Interstitial cystitis (also known as painful bladder syndrome) is a chronic bladder condition that is 10 times more common in women than men. It is characterised by pain, urinary urgency and frequency, and nocturia. There are cystoscopic and histological features that are said to be typical of interstitial cystitis. However, in many cases the diagnosis is made by exclusion, once specific causes such as infection and malignancy have been ruled out (Dawson and Jamison 2007).

Treatments for interstitial cystitis include dietary and lifestyle interventions, oral medication, intravesical instillations and, in some cases, surgery. No single treatment is effective for all subtypes or phenotypes.

Regulatory status of dimethyl sulfoxide bladder instillation

Dimethyl sulfoxide (DMSO) bladder instillation is unlicensed in the UK. A 50 ml solution of 50% DMSO for intravesical instillation (Rimso-50) is licensed by the US Food and Drug Administration. It is available from 'special-order' manufacturers or specialist importing companies.

In line with the guidance from the General Medical Council (GMC), it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using DMSO.

Evidence statements

  • Three small randomised controlled trials (RCTs) were identified for inclusion in this evidence summary. One of the RCTs (Perez-Marrero et al. 1988) compared DMSO with placebo and 2 (Peeker et al. 2000 and Sairanen et al. 2009) compared DMSO with bacillus Calmette-Guerin (BCG) (off-label use). It should be noted that the European Association of Urology 2012 guidelines on chronic pelvic pain concluded that bladder instillation with BCG is not effective for the treatment of bladder pain syndrome/interstitial cystitis and its use for this indication is not recommended.

  • A Cochrane review on intravesical treatments for painful bladder syndrome/interstitial cystitis (Dawson and Jamison 2007) [search date 2006] included 1 of these studies (Perez-Marrero et al. 1988). The Cochrane review also identified the Peeker et al. (2000) study but concluded that it did not provide useful data for any outcome and did not provide data that contributed to the Cochrane review (see Evidence strengths and limitations).

  • Perez-Marrero et al. (1988) was a small randomised crossover trial that compared DMSO with placebo (saline) in 33 people with biopsies suggestive of interstitial cystitis. More people reported a marked subjective improvement with DMSO than with placebo (6/15 [40%] compared with 3/17 [18%]; reported as statistically significant; no p value given). The Cochrane review (Dawson and Jamison 2007) presented statistical analysis that was not available in the published study. This reported no statistically significant difference between DMSO and placebo for maximum cystometric capacity (the volume at which a person is unable or unwilling to tolerate continued bladder filling or leakage occurs) [mean difference 17.00 ml; 95% confidence interval [CI] −11.22 to 45.22] or the number of people whose pain resolved at maximum cystometric capacity (23/28 compared with 22/28; odds ratio [OR] 0.22; 95% CI −1.10 to 1.55).

  • Sairanen et al. (2009) was a 3-month randomised open-label trial comparing instillations with DMSO to instillations with BCG in 75 people with painful bladder syndrome/interstitial cystitis. The main aim of the study was to evaluate a health-related quality of life questionnaire. At the 3-month follow-up, more people had a global assessment of treatment response of 'much better' or 'completely cured' with DMSO compared with BCG (11/37 [30%] compared with 4/38 [11%]; p<0.05).

Summary of the evidence

This section gives a brief summary of the main evidence. A more thorough analysis is given in the Evidence review section.

Efficacy

This evidence summary is based on 3 small RCTs. One compared DMSO with placebo (saline) (Perez-Marrero et al. 1988) and 2 (Peeker et al. 2000 and Sairanen et al. 2009) compared DMSO with BCG (off-label use). A Cochrane review on intravesical treatments for painful bladder syndrome/interstitial cystitis (Dawson and Jamison 2007) [search date 2006] included 1 of these studies [Perez-Marrero et al. (1988)]. The Cochrane review also identified the Peeker et al. (2000) study but concluded that it did not provide useful data for any outcome and did not provide data that contributed to the Cochrane review (see Evidence strengths and limitations).

Dimethyl sulfoxide compared with placebo (saline)

Perez-Marrero et al. (1988) was a crossover trial in 33 people (30 women; mean age 48 years) with biopsies suggestive of interstitial cystitis. People were randomised to receive 4 instillations, 2 weeks apart, of either DMSO (50 ml of 50% DMSO) or placebo (50 ml of normal saline) (phase I). Participants were asked to hold the solution in their bladder for at least 15 minutes. After a 4-week washout period the treatment allocation was reversed and a further 4 instillations given (phase II).

Participants were divided into groups of 15 (DMSO first) and 18 (placebo first) that were statistically comparable in age, severity and duration of symptoms. The method of randomisation and whether randomisation was concealed was not reported. One patient in the placebo first group was found to be pregnant shortly after the first saline instillation and was removed from the study. Two patients in the placebo-first group dropped out before phase II of the trial.

Assessment followed the completion of each treatment phase and comprised a subjective assessment by participants (participants were asked to rate their treatment response as minimal [0], moderate or marked) and an objective outcome based on 3 urodynamic parameters (see table 1 for description of urodynamic parameters used). Improvement in urodynamic parameters had to be accompanied by improvements in voiding (maximum voided volume or number of nocturia episodes) and/or visual analogue scale (VAS) scores for pain, and urinary urgency and frequency to be considered valid. Participants were blinded to treatment allocation but the garlic halitus (breath smelling of garlic) caused by DMSO bladder instillation makes blinding difficult to maintain. Assessors for the objective outcome were blinded to treatment allocation.

At the completion of phase I, 93% (14/15) of the people treated with DMSO were considered objectively to have experienced improvement compared with 35% (6/17) of the placebo group. No statistical analysis was presented. After crossover, at the completion of phase II, 86% of people initially treated with DMSO at phase I continued to show objective improvement from baseline (13/15). When the placebo group crossed over to DMSO at phase II, 67% of people showed an objective improvement (10/15).

At the completion of phase I, 40% (6/15) of people treated with DMSO and 18% (3/17) of people receiving placebo reported marked subjective improvement in symptoms. The difference in the proportion of people reporting marked subjective improvement was reported to be statistically significant but no statistical analysis was presented. People in the group who received DMSO at phase I continued to report subjective improvement after treatment with placebo at phase II, with 53% (8/15) reporting marked improvement. When the placebo group crossed over to DMSO at phase II, 47% of people (7/15) reported marked improvement.

A Cochrane review on intravesical treatments for painful bladder syndrome/interstitial cystitis (Dawson and Jamison 2007) [search date 2006] included Perez-Marrero et al. (1988) and presented statistical analysis for 2 of the urodynamic parameters that was not available in the published study. The Cochrane review reported that there was no statistically significant difference between DMSO and placebo for maximum cystometric capacity (mean difference 17.00 ml; 95% confidence interval [CI] −11.22 to 45.22) or the number of people whose pain resolved at maximum cystometric capacity (23/28 compared with 22/28; odds ratio [OR] 0.22; 95% CI −1.10 to 1.55).

Table 1 Summary of Perez-Marrero et al. (1988)

Group A

Group B

Analysis

Randomised

n=15

n=18

Phase I

DMSO

Placebo

Efficacy

n=15

n=17a

Objective improvementb

93% (14/15)

35% (6/17)

No statistical analysis presented

Subjective marked improvement

40% (6/15)

18% (3/17)

Reported to be statistically different, p value not reported

See also Cochrane review: additional statistical analysisc

Subjective moderate improvement

47% (7/15)

41% (7/17)

Phase II

Placebo

DMSO

Efficacy

n=15

n=15d

Objective improvement

86% (13/15)

67% (10/15)

Subjective marked improvement

53% (8/15)

47% (7/15)

Subjective moderate improvement

33% (5/15)

20% (3/15)

Cochrane review: additional statistical analysisc

DMSO (given as initial or second instillation)

Placebo (given as initial or second instillation)

Pain resolved at maximum cystometric capacity

23/28

22/28

No statistically significant difference between DMSO and placebo (OR 0.22; 95% CI −1.10 to 1.55)

Maximum cystometric capacity

-

-

No statistically significant difference between DMSO and placebo (mean difference 17 ml; 95% CI −11.22 to 45.22 ml)

Safety

Patients reporting serious adverse events

2 severe (1 hemiparesis, 1 migraine) both in placebo phase

Abbreviations: CI, confidence interval; DMSO, dimethyl sulfoxide; n, number of patients; OR, odds ratio.

a One patient was found to be pregnant shortly after the first instillation (placebo) and was removed from the study.

b Objective improvement was based on 3 urodynamic parameters (improvement by 50% in cystometric urge [the volume at which a person has a strong desire to void but can tolerate continued bladder filling] or maximum cystometric capacity [the volume at which a person is unable or unwilling to tolerate continued bladder filling or leakage occurs] and/or the disappearance of suprapubic pain or urethral pain at maximum cystometric capacity). Improvement in urodynamic parameters had to be accompanied by improvements in voiding (maximum voided volume or number of nocturia episodes) and/or visual analogue scale scores for pain, and urinary urgency and frequency to be considered valid.

c A Cochrane review on intravesical treatments for painful bladder syndrome/interstitial cystitis (Dawson and Jamison 2007) includes Perez-Marrero et al. (1988) and presents statistical analysis for 2 of the urodynamic parameters that was not available in the published study.

d Two patients dropped out between phase I and phase II.

Dimethyl sulfoxide compared with bacillus Calmette-Guerin

It should be noted that the European Association of Urology 2012 guidelines on chronic pelvic pain concluded that bladder instillation with BCG is not effective for the treatment of interstitial cystitis/bladder pain syndrome and that its use for this indication is not recommended. The use of BCG for interstitial cystitis is off-label.

Peeker et al. (2000) was described as a double-blind crossover RCT. However, it was not a true crossover design because participants only crossed over to the second treatment if they did not improve with the first treatment they were randomised to. Twenty-one participants (20 women) were included, of whom 11 (mean age 59 years) had classic or ulcerative interstitial cystitis and 10 (mean age 43 years) had non-ulcerative interstitial cystitis (based on clinical, endoscopic and histopathological criteria). The trial compared 6 weekly instillations with BCG (retained in the bladder for 2 hours) with 6 weekly instillations of DMSO (50 ml of 50%, duration of retention not reported). Participants not reporting subjective improvement after receiving the first treatment crossed over to the other treatment after a washout period of at least 7 weeks. Analysis of outcomes took place at the end of this washout period.

The primary outcome was subjective improvement (not further defined). The effect of treatment on maximal functional bladder capacity, urinary frequency (both assessed according to patient voiding diaries) and pain (VAS scores) was also reported.

Participants were divided into 2 groups. The number of participants randomised to each group and the number with each type of interstitial cystitis was not given, and the method of randomisation was not reported. It is unclear whether randomisation was concealed. Participants were blinded to treatment allocation but the garlic halitus (breath smelling of garlic) caused by DMSO bladder instillation makes blinding difficult to maintain.

The Cochrane review (Dawson and Jamison 2007) identified this study as part of the systematic review but because insufficient information was provided to allow parallel analysis of the first period of the trial, data from this study did not contribute to the review (see Evidence strengths and limitations).

Two participants who received DMSO as the initial treatment reported improvement and so did not cross over to BCG (no individual data or statistical analysis were presented). None of the participants who received BCG as the initial treatment reported improvement. However, 4 participants in this group withdrew without having crossover treatment despite not improving. Therefore 6 participants received 1 treatment only and 15 participants received both treatments. Apart from these 6 participants it is not possible to confirm group size or order of treatment from the data presented. A further 5 people reported improvement after crossing over to DMSO. The majority of people whose condition responded to treatment were in the group that received BCG first followed by DMSO. It is not clear whether the washout period used in this study was long enough. It has been reported that a 6-month follow-up after treatment with BCG is needed to define response.

Of the 7 people who reported improvement, 2 remained symptom-free for 12 and 18 months and the remaining 5 relapsed and continued treatment with DMSO. It was not reported whether the participants who showed improvement had ulcerative or non-ulcerative interstitial cystitis.

Sairanen et al. (2009) was a 3-month randomised open-label trial in 75 people (71 women; mean age 59 years) meeting National Institute of Diabetes and Digestive and Kidney Diseases criteria for painful bladder syndrome/interstitial cystitis. It compared intravesical instillations of 50 ml 50% DMSO with 50 ml Tice strain BCG (dose of BCG not reported, length of instillation not reported) given once a week for 6 weeks. The main aim of the study was to evaluate a health-related quality of life (HRQoL) questionnaire in painful bladder syndrome/interstitial cystitis.

Participants were randomised into 2 groups: 37 to DMSO and 38 to BCG. The method of randomisation and whether randomisation was concealed was not reported. The primary outcome of the study was alleviation of pain. However, data for this outcome were not reported. Data were reported on subjective global assessment of treatment response after 3 months, with the condition of participants who scored their response as much better or completely cured considered to have responded to treatment. The HRQoL questionnaire (which included questions relating to general health perceptions, pain, emotional wellbeing, vitality, social functioning, physical capacity and sexual interest and functioning) was also completed before treatment and at the 3-month follow-up.

At the 3-month follow-up, more people had a global assessment of treatment response of 'much better' or 'completely cured' with DMSO compared with BCG (11/37 [30%] compared with 4/38 [11%]; p<0.05). After 3 months, if subjective treatment response was not achieved, participants were allowed to cross over to the other treatment group without any specified washout period. A new baseline HRQoL questionnaire and a new outcome questionnaire were obtained at 3 months. DMSO and BCG therapies were reported to have an equal effect on HRQoL (p value not reported).This analysis combined results after the first instillation therapy with results for participants who had received secondary treatment with DMSO or BCG (without a specified washout period) if their condition had not responded to the initial treatment they were allocated to.

Safety

Adverse events reported in trials

In Perez-Marrero et al. (1988), adverse events were seen in 5 people (15%). Three were minor (2 uncomplicated lower urinary tract infections, 1 case of biliary colic). It was unclear whether participants were receiving placebo or DMSO at the time of the adverse event. The other 2 adverse events were severe (1 hemiparesis, 1 migraine). Both of these occurred during the placebo phase and resolved completely within 48 hours.

In Peeker et al. (2000) adverse events after DMSO treatment were reported as increased urinary urgency (2 cases) and dysuria (3 cases).

Adverse events were not reported in Sairanen et al. (2009).

Other sources of safety information

Adverse reactions associated with Rimso-50 (50% DMSO instillation licensed by the US Food and Drug Administration) listed in the prescribing information are a garlic-like taste and odour on the breath and skin, which may remain for 72 hours, and transient chemical cystitis. Administration may cause moderately severe discomfort. DMSO may cause a hypersensitivity reaction (reported in 1 patient receiving intravesical Rimso-50 solution). Full eye evaluations including slit lamp examinations are recommended before and periodically during treatment. Biochemical screening, particularly liver and renal function tests, and complete blood count should be done approximately every 6 months. Intravesical instillation of Rimso-50 solution may be harmful to people with urinary tract malignancy because of dimethyl-sulfoxide-induced vasodilation.

The British national formulary (December 2013) states that bladder spasm and hypersensitivity reactions may occur with DMSO and long-term use requires ophthalmic, renal, and hepatic assessment at intervals of 6 months. It also recommends that the concomitant use of DMSO with the non-steroidal anti-inflammatory drug sulindac should be avoided.

The European Association of Urology 2012 guidelines on chronic pelvic pain state that use of DMSO is contraindicated during urinary tract infections or shortly after bladder biopsy.

Cost effectiveness and cost

No cost effectiveness studies were identified.

Because DMSO bladder instillation (Rimso-50) is unlicensed in the UK, no costs could be obtained from standard published sources or the manufacturer. It is available from 'special-order' manufacturers or specialist importing companies. Informal sources suggest that the cost is around £101 (plus VAT) per 50 ml bladder instillation.