bladder pain syndrome / interstitial cystitis ( bps / ic ) is a clinical diagnosis primarily based on symptoms of urinary urgency , frequency , and suprapubic or pelvic pain .
the prevalence of bps / ic ranges from 10 to up to 510 cases per 100,000 population .
the etiology of bps / ic is so far unknown , with several theories under discussion , including an autoimmune response , mast cell activation , neuropathic changes , occult infection , toxic substances in the urine , and a primary defect in the glycosaminoglycan ( gag ) layer of the bladder mucosa .
prominent among the theories is that bps / ic may be related to a primary defect of the gag layer of the bladder urothelium .
the major classes of gags include hyaluronic acid , heparin sulfate , heparin , chondroitin 4-sulfate and chondroitin 6-sulfate , dermatan sulfate , and keratan sulfate .
hyaluronic acid contributes an important proportion of the gags of the bladder surface and is considered a good candidate for gag substitution in patients with bps / ic .
gag substitution therapy with hyaluronic acid has been shown to benefit patients by relieving the distressing symptoms of pain , urinary frequency , urgency , nocturia , and hematuria .
for intravesical hyaluronic acid therapy , several uncontrolled studies using 40 mg dissolved in 40 ml of normal saline solution weekly for 4 to 6 weeks and then monthly thereafter have reported response rates varying from 71% to 30%   in bps / ic as well as in other chronic inflammatory bladder diseases such as radiation and recurrent bacterial cystitis . however , like the other treatment options for patients with bps / ic , intravesical hyaluronic acid therapy has no long - term efficacy and its benefits on bps / ic symptoms decrease in 24 weeks . on the other hand , up to 70% of patients treated with intravesical hyaluronic acid
several studies have evaluated the bladder distension with electromotive drug administration ( emda ) in patients with bps / ic , and the findings of these studies suggest that office distention with emda is a viable alternative for select ic patients .
, results in patients with t1 bladder cancer improved in patients administered bacille calmette - gurin ( bcg ) and mitomycin via emda compared with the group administered bcg alone . electromotive mitomycin increases tissue uptake compared with passive diffusion . given that instillation of hyaluronic acid via emda may increase tissue uptake and improve efficacy
, we designed the present randomized prospective study to evaluate whether intravesical hyaluronic acid installation with emda would improve the response rate and long - term efficacy of the therapy .
within the time period of 2004 - 2005 , 31 patients who had been diagnosed with bps / ic were examined .
inclusion criteria were as follows : all patients fulfilled the national institute of diabetes and digestive and kidney diseases criteria for bps / ic , no other treatments were allowed during the study , and patients had been evaluated for urinary tract infection and it had been ruled out .
exclusion criteria were as follows : any other medication for ic during the study period , neurogenic bladder , history of pelvic surgery or trauma to the pelvic region , presence of active urinary tract infection , frequency of urination less than 8 times / d , presence of bladder or lower ureteral calculi , presence of benign or malignant bladder tumors , presence of active genital herpes infection , or presence of chemical or radiation cystitis .
a , patients were treated with 40-mg intravesical hyaluronic acid ( cythyal , bioscience gmbh , pontiac , mi , usa ) administered via a hydrophilic 12-fr foley catheter and were instructed to retain the installation volume for at least 60 minutes . in group b ,
patients were catheterized with a 16-fr ( ce - das orugenics / ag 9701 , mirandola , mo , italy ) catheter ( special catheter for emda with a spiral silver electrode in the first part ) , and 40-mg hyaluronic acid in 40-ml saline was instilled into the bladder by gravity .
two patch electrodes were placed in the suprapubic region by using an ample amount of contact gel to avoid burns .
the electrodes were taped tightly in place to achieve good contact and to prevent dispersion of current over the abdomen .
emda was then performed by using the current generator with the following parameters : polarity positive , rise rate 30 - 60 ma / s , peak current 60 ma , pulsed output , and treatment time 25 minutes . in both groups , instillations were performed weekly in the first month and then monthly after 2 months .
urine analysis was performed for all patients and active urinary tract infection was ruled out .
all patients followed the same diet controls ( no caffeine , alcohol , or beverages that might acidify the urine , such as cranberry juice or orange juice ) during their treatment and follow - up . potassium sensitivity test performed in all patients before treatment .
cystoscopy with hydrodistention was performed before treatment in all patients and the presence of hunner ulcers was noted .
baseline voiding symptoms were recorded in 2-day voiding diaries , a visual analogue scale ( vas ) was used to assess worst pain , and ic symptom and problem indexes were used to assess ic . at visits at 1 , 6 , 12 , and 24 months , the patients returned 2-day voiding diaries , marked the vas score , filled out the symptom and problem questionnaires , and gave the global response assessment ( gra ) .
the gra was defined as follows : 1 , worse ; 2 , no change ; 3 , slightly better ; 4 , moderately better ; 5 , much better ; and 6 , completely cured .
the parameters used for assessment of treatment response were based on the study by propert et al . .
the physicians who assessed the treatment response were blinded to the patients ' means of application of hyaluronic acid .
the primary end points of the study were vas score , gra , and micturition frequency in 24 hours .
secondary end points were mean voided volume , number of nocturia episodes , and ic symptom and problem scores .
randomization was performed by the block randomization method and ncss software ( ncss , kaysville , ut , usa ) was used .
sample size was estimated as 25 with a power of 0.80 and an effect size of 50% ( 3 points of decrease in vas score ) .
baseline factors were compared with the t - test and differences between treatment outcomes were calculated with the student t - test .
the paired - samples t - test was used to compare treatment results of a single group in certain time intervals .
multivariable cox proportional hazards regression was performed to determine any factor predictive of treatment response .
of the 31 patients enrolled , 25 patients were female and 6 patients were male .
there were 15 ( 3 males and 12 females ) patients in group a , and 16 ( 3 males and 13 females ) patients in group b. there were no significant differences in baseline characteristics between the groups ( table 1 ) . during cystoscopy , hunner ulcers were observed in 3 and 4 patients in groups a and b , respectively .
oral pentosan polysulfate had been prescribed to 6 patients in group a and 9 patients in group b previously and those patients did not respond to pentosan polysulfate .
also , 8 patients in group a and 8 patients in group b had a history of intravesical heparin therapy .
none of the patients experienced any serious adverse events and no patients refused treatment related to side effects .
treatment responses in both groups were compared at certain time intervals and are summarized in table 2 .
both treatment arms were successful at months 6 and 12 compared with baseline in all parameters , but group b was found to have statistically better results in those given time intervals . however , both groups were found to have no statistically significant improvement at month 1 compared with baseline . at month 24 , voiding frequency and vas were the only parameters that were significantly improved compared with baseline in both groups , and there were no statistically significant differences between the groups .
the results of the multivariable cox proportional hazards regression showed that treatment with emda , positive kcl test result , and voiding frequency > 17 were associated with higher response rates .
the other parameters involved in the multivariate analysis were not found to be associated with higher response rates .
because of its uncertain cause and pathogenesis , there is currently no cure for bps / ic and the goal of therapy is symptomatic relief .
improvement can be attained with several treatment options , including oral therapy ( e.g. , pentosan polysulfate sodium ) , intravesical therapy ( e.g. , gag substitution therapy with specific agents ) , and even surgical interventions , although relapses are common .
gag substitution therapy with hyaluronic acid in patients with bps / ic has been evaluated in previous studies .
explaining the mechanism of hyaluronic acid treatment in patients with bps / ic as just the reconstitution of a morphologically defective gag layer may not be exactly right .
hyaluronic acid has various biological activities including inhibiting the adherence of immune complexes to polymorphonuclear cells , marked inhibition of leukocyte migration and aggregation depending on viscosity , regulation of fibroblast and endothelial cell proliferation , enhancement of connective tissue healing , and creation of a barrier over membranes , thus regulating movement of solutes .
all of the biological activities listed above may contribute to the action of hyaluronic acid in interstitial cystitis .
reports in the literature of treatment results with long - term follow - up differ . in a study by morales et al . , the complete or partial response rate of intravesical hyaluronic acid treatment for up to 1 year was 71% ; however , beyond week 24 there was a moderate decrease in the response rate of the medication . in a danish
open and uncontrolled pilot study , 20 patients with bps / ic received weekly bladder instillations of hyaluronic acid for 1 month and monthly instillations for an additional 2 months .
the patients were then offered further monthly instillations , and all patients were evaluated after 3 years . in contrast with the morales et al .
's study , the danish study showed long - term efficacy of intravesical hyaluronic acid therapy .
three years after the initiation of treatment , 65% of patients ( 13 of the 20 patients ) still responded to treatment in terms of symptom remission and pain score reduction .
the patients in the danish study received a longer duration of intravesical hyaluronic acid therapy ( monthly for 3 years vs. 1 year ) .
we think that the difference in these long - term efficacy results may be due to the longer duration of intravesical hyaluronic acid in the danish study .
treatment results with long - term follow - up were also recently reported by engelhardt et al . .
in that study , 24 of the 48 patients were evaluated after 5 years , and 20 of these patients reported decreased pain .
several studies have reported that installation of the agent into the bladder with emda improves the treatment efficacy in patients with bladder cancer and bps / ic .
compared mitomycin delivery between passive diffusion and electromotive administration in high - risk patients with superficial bladder cancer .
peak plasma concentrations of mitomycin were 5.5 times higher in patients who underwent electromotive delivery than in those who underwent passive diffusion , which suggests that the cells of the bladder wall were exposed to incremental concentrations of this magnitude .
the median time to first recurrence of a tumor was nearly doubled with electromotive delivery compared with passive diffusion and was similar to bcg alone - a third comparator group . in another study by di stasi et al .
, the investigators randomly assigned 212 patients with pathological t1 bladder cancer to bcg alone or bcg and electromotive mitomycin .
they concluded that the bcg and electromotive mitomycin group had significantly fewer progressions and deaths from bladder cancer . performing emda in patients with
lidocaine and dexamethasone installation with emda followed by cystodistention in 21 women showed a 25% success rate up to 6 months after instillation . using a similar technique , riedl et al .   noted complete resolution of bladder symptoms in 61% of patients ( 8 of 13 ) .
in a study by rose et al . , bladder distention with two different anesthetic strategies was evaluated : simple instillation of alkalized lidocaine and emda of lidocaine .
those authors concluded that lidocaine emda is superior to alkalized lidocaine in that it allows for a greater distention of the bladder for a longer period of time . in another study by the same group of authors , comparison between bladder distension with lidocaine emda and distension with general or spinal anesthesia
in the present study , there was significant improvement in both treatment arms at months 6 and 12 compared with baseline in terms of micturition frequency , mean voided volume , number of nocturia episodes , ic symptom and problem scores , vas score , and gra .
furthermore , this improvement in group b ( hyaluronic acid instilled via emda ) was significantly higher than that in group a ( hyaluronic acid instilled via hydrophilic 12-fr foley catheter ) for all parameters listed .
this may mean that emda improves the efficacy of hyaluronic acid in patients with bps / ic as a result of increasing the tissue uptake of hyaluronic acid compared with that after installation with a hydrophilic catheter .
additionally , morales et al .   stated that the effectiveness of hyaluronic acid therapy decreased after 24 weeks .
however , in our study group at 1 year , there was still significant improvement in all parameters with lower - dose hyaluronic acid than in the morales et al .
this may relate to different groups of patients with different bps / ic pathogenesis . at month 24 , the effectiveness of the therapy was decreased , and voiding frequency and vas were the only parameters that were significantly improved compared with baseline in both groups . at this point ,
the installation with emda group showed superiority to group a. the findings of the present study may suggest that emda improves hyaluronic acid efficacy ; however , it does not increase the duration of efficacy .
the number of patients in the study was low , and the findings should be confirmed in multicenter trails with a higher number of patients .
lack of a control group is a considerable limitation of the study ; however , other studies of hyaluronic acid therapy have shown favorable findings in patients with bps / ic .
on the other hand , we think that it is not ethical to treat this group of patients with placebo for a long time period .
plasma concentrations of hyaluronic acid could be determined in both groups ; however , there were studies showing that emda increases the plasma concentration of the agent , so we did not perform this measurement .
hyaluronic acid installation is an effective gag substitution therapy in patients with bps / ic . instilling hyaluronic acid via emda
can improve the efficacy of the treatment ; however , lack of long - term efficacy is the major problem of this gag substitution therapy .
 purposein the treatment of interstitial cystitis , intravesical hyaluronic acid application may be suggested as a treatment option . in this randomized prospective study , 
 the authors aimed to identify whether instilling the hyaluronic acid with electromotive drug administration ( emda ) would increase the tissue uptake and improve the efficacy.materials and methodsthe data of 31 patients who had been diagnosed with bladder pain syndrome / interstitial cystitis ( bps / ic ) between 2004 and 2005 were examined . 
 the patients were randomized to two groups : patients in group a received hyaluronic acid directly with a catheter and patients in group b received hyaluronic acid with emda . 
 the patients were followed for 24 months and the two groups were compared at certain time intervals . 
 the primary end points of the study were visual analogue scale ( vas ) score , global response assessment , and micturition frequency in 24 hours.resultsthere were 6 males and 25 females . 
 the two groups were similar in baseline parameters . 
 the decrease in vas score and the micturition frequency in 24 hours were significantly lower with emda at months 6 and 12 . 
 the difference between the two groups was not significant at months 1 and 24 . also , 
 treatment with emda , positive kcl test , and pretreatment voiding frequency > 17 were associated with higher response rates.conclusionshyaluronic acid installation is an effective glycosaminoglycan substitution therapy in patients with bps / ic . 
 instillation of hyaluronic acid via emda can improve the efficacy of the treatment ; however , lack of long - term efficacy is the major problem with this glycosaminoglycan substitution therapy . 