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Interstitial cystitis/painful bladder syndrome (IC/PBS) is a debilitating chronic disease of unknown aetiology characterized by frequency, nocturia and suprapubic pain at full bladder. Current treatments are usually unsuccessful in completely eradicating bladder pain and increasing bladder capacity . Other intravesical therapies such as hyaluronic acid, BCG, and oral medications with pentosan polysulphate (PPS), cyclosporin A, or amitriptyline have not shown long-term effectiveness [2–4]. At present, bladder hydrodistention (HD) is still the most common treatment for IC/PBS in some countries but the therapeutic duration was short .
Although satisfactory efficacy of botulinum toxin type A (BoNT-A) in the treatment of detrusor overactivity has been widely reported [6,7], there have only been a few studies using BoNT-A in treatment of IC/PBS [8–10]. In recent basic research, BoNT-A was shown to inhibit not only the release of acetylcholine and norepinephrine, but also that of nerve growth factor, ATP, substance P and calcitonin gene-related peptide from the urothelium and in nerve fibres [11–13]. In clinical experiments, BoNT-A has been shown to decrease detrusor overactivity, bladder sensation, and visceral pain in chronic inflammatory diseases [6–10,14]. These results suggest that BoNT-A treatment can modulate sensory transmission as well as reduce detrusor contractility. Although BoNT-A injection seems to be a promising treatment for the symptoms of IC/PBS, long-term outcomes were not successful in a previous study .
The present study was designed to evaluate the clinical effectiveness of intravesical injection of BoNT-A followed by cystoscopic HD in patients with IC/PBS. Patients who received HD alone served as the control group.
PATIENTS AND METHODS
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Patients with IC/PBS who had failed conventional treatments were enrolled in this study. A diagnosis of IC/PBS had been established based on characteristic symptoms of suprapubic pain related to bladder filling, accompanied by daytime and night-time frequency and cystoscopic findings of glomerulation, petechia, or mucosal ulceration . All patients had been treated with oral PPS, intravesical instillation of heparin, hyaluronic acid, or tricyclic antidepressant for ≥6 months but the symptoms remained unchanged or relapsed. Patients were investigated thoroughly before enrolment and were excluded if they did not meet the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) criteria for IC/PBS in their initial assessment .
Patients were requested to keep a 3-day voiding diary before treatment, which recorded functional bladder capacity (FBC) and the number of episodes of urinary frequency and nocturia. The IC/PBS symptoms were assessed by the O’Leary-Sant IC Symptom Index (ICSI) and IC Problem Index (ICPI) . The pain score was reported by patient self-assessment using a 10-point visual analogue scale (VAS) system. Video-urodynamic study and KCl sensitivity tests were performed. Before treatment, patients were informed of the possible complications associated with BoNT-A injection such as generalized muscle weakness, difficult urination, transient urinary retention, or UTIs.
This study was approved by the Institutional Review Board and Ethics Committee of the university. Each patient was informed about the study rationale and procedures, and written, informed consent was obtained before treatment.
Patients were admitted to the hospital for treatment. They were randomly assigned to receive any one of the following three therapies: (i) intravesical injection of 200 U of BoNT-A (BOTOX, Allergan, Irvine, CA, USA) under i.v. general anaesthesia in the operation room (BoNT-A200U group), (ii) intravesical injection of 100 U of BoNT-A (BoNT-A100U group), and (iii) cystoscopic HD alone (HD group).
Patients treated with BoNT-A received suburothelial injections. The injection needle was inserted about 1 mm into the urothelium at 40 sites in the posterior and lateral walls of the bladder. Each injection site received 5 U and 2.5 U in 0.5 mL for patients who received 200 U and 100 U BoNT-A, respectively, using a 23-G needle and rigid cystoscopic injection instrument (22 F, Richard Wolf, Knittlingen, Germany).
After the BoNT-A injections, a 14 F urethral Foley catheter was placed for 1 day and patients were discharged on the next day. Oral antibiotics were prescribed for 7 days. Patients were seen in the outpatient clinic 2 weeks later. Stable medication with PPS was continued as taken before this treatment. The 3-day voiding diary, ICSI, ICPI and pain VAS were recorded.
At 2 weeks after BoNT-A injections, patients underwent cystoscopic HD under general anaesthesia. Cystoscopic HD was performed to an intravesical pressure of 80 cmH2O for 15 min and the maximal bladder capacity (MBC) under HD was recorded. Patients in the HD group underwent cystoscopic HD alone using the similar methods as in the BoNT-A groups. The MBC of HD at the diagnosis of IC/PBS was regarded as the baseline MBC value.
During each follow-up visit, data from the 3-day voiding diary, ICSI, ICPI, as well as information on FBC, daily urinary frequency, nocturia and pain VAS were recorded. The largest voided volume in the 3-day voiding diary was considered as a measure of FBC. The primary end-point was assessment at 3 months after HD and follow-up assessment was performed at 3-month intervals until patients felt recurrence of baseline symptoms.
Urodynamic study was performed at baseline and 3 months after HD treatment. The urodynamic study was performed by standard procedures using a 6 F dual-channel catheter and an 8 F rectal balloon catheter. Cystometry was performed with normal saline at 20 mL/min.The urodynamic variables assessed included first sensation of bladder filling, urge sensation, cystometric bladder capacity (CBC), detrusor pressure, maximum urinary flow rate during voiding and postvoid residual urine volume (PVR).
The treatment outcome was assessed using the global response assessment (GRA) [3,4]. Patients were requested to rate symptoms compared with baseline on a 7-point centred scale from ‘markedly’, ‘moderately’ and ‘slightly worse’, ‘no change’, to ‘slightly’, ‘moderately’ and ‘markedly improved’. Patients with moderately and markedly improved results after treatment were considered to have a successful treatment outcome. Otherwise, the treatment was considered to have failed.
The results of the voiding diary, urodynamic study, ICSI, ICPI score and pain VAS were compared between baseline and 3 month after HD treatment, and among the two BoNT-A and control groups. Long-term successful outcome was assessed based on the GRA. Student’s paired t-test was used for statistical analysis within groups and anova with post hoc analysis was used for statistical analysis among groups; P < 0.05 was considered to indicate statistical significance.
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In all, 70 patients were randomized to BoNT-A200U, BoNT-A100U or HD group. Two patients in the BoNT-A200U group and one in the HD group refused treatment at the day it was scheduled, leaving 56 women and 11 men who were included in the final analysis. There was no active UTI in any patient at the time of enrolment.
During the first year of the trial, nine of 15 patients in the BoNT-A200U group developed severe dysuria (seven), large PVR (five), chronic urinary retention (two) or UTI (three) and the study protocol was therefore changed at the 1-year point due to safety considerations. Six patients originally assigned in BoNT-A200U group were re-assigned to the 100 U group. Thus, during the study period 15 patients received 200 U BoNT-A plus HD, 29 received 100 U BoNT-A plus HD and 23 received HD alone. The mean (sd, range) duration of IC/PBS at the time of enrolment was 8 (5, 2–15) years. The mean (sd, range) age of the patients was 45.7 (12.5, 26–68), 47.7 (14.7, 26–84) and 52.5 (15.3, 30–83) years in the BoNT-A200U, BoNT-A100U and HD group, respectively. There were no significant difference in the disease duration and age among the three groups.
The mean (sd) MBC at the time of diagnosis of IC/PBS was 646 (196) mL, 589 (182) mL and 619 (141) mL for BoNT-A100U, BoNT-A200U and HD group, respectively (P = 0.186). In the initial 2 weeks after BoNT-A injection, two patients in the BoNT-A groups developed gross haematuria, 12 had difficult urination including three with transient urinary retention, and UTI occurred in three patients. In the HD group, no patient developed difficult urination or haematuria in the initial 2 weeks after treatment.
Among the 44 patients who received BoNT-A injections and HD, 12 of the 15 patients in the BoNT-A200U group and 21 (72%) in the BoNT-A100U group had a successful result based on GRA at 3 months. By contrast, only 11 (48%) patients in the HD group had improvement (P = 0.032). The mean (sd) MBC had increased by 21% in the BoNT-A200U group from 589 (182) to 714 (175) mL (P = 0.001), and by 24% in the BoNT-A100U group from 646 (196) to 802 (228) mL (P < 0.001) during HD 2 weeks later (P = 0.703). At 3 months, the ICSI and ICPI scores had decreased significantly in all three groups, but the changes among them were not significant. Pain VAS score had decreased by 39%, 55% and 18% (P = 0.007), and FBC had increased by 17%, 68% and 9% (P = 0.05) in the BoNT-A100U, BoNT-A200U and HD group at 3 months, respectively (Table 1).
Table 1. Changes of voiding diary, IC symptom scores, pain VAS and urodynamic variables at baseline and 3 months among three groups of patients
|Variable||BoNT-A 100 U||BoNT-A 200 U||HD|
|N|| 29|| 15|| 23|
|Mean (sd):|| || || |
| FBC, mL|| || || |
| Baseline||161.0 (97.4)||113.9 (58.0)||134.0 (72.4)|
| 3 months||189.0 (78.8)||190.8 (80.6)*||145.5 ( 77.4)|
| Daytime frequency, n|| || || |
| Baseline|| 13.0 (4.69)|| 14.2 (5.44)|| 11.6 (4.36)|
| 3 months|| 9.72 (4.03)|| 9.40 (3.22)*|| 9.96 (3.97)|
| Nocturia, n|| || || |
| Baseline|| 3.41 (2.16)|| 6.33 (6.96)|| 3.70 (2.03)|
| 3 months|| 2.59 (1.97)|| 3.13 (2.47)|| 3.52 (2.15)|
| ICSI|| || || |
| Baseline|| 12.5 (2.15)|| 13.9 (2.53)|| 12.8 (3.41)|
| 3 months|| 8.17 (4.06)*|| 8.9 (5.58)*|| 9.87 (4.85)*|
| ICPI|| || || |
| Baseline|| 11.1 (2.05)|| 12.3 (1.40)|| 11.1 (2.60)|
| 3 months|| 6.93 (3.58)*|| 7.13 (4.52)*|| 8.57 (4.59)*|
| Pain VAS|| || || |
| Baseline|| 4.83 (2.21)|| 5.47 (2.1)|| 4.30 (2.60)|
| 3 months|| 2.97 (1.99)*|| 2.47 (2.1)*|| 3.52 (3.07)|
|Urodynamic|| || || |
| First sensation of filling, mL|| || || |
| Baseline||140.5 (48.5)||157.3 (63.5)||135.3 (46.9)|
| 3 months||176.8 (58.5)*||181.1 (76.4)||139.1 (58.4)|
| Urge, mL|| || || |
| Baseline||263.9 (89.5)||237.3 (70.1)||248.2 (75.8)|
| 3 months||301.8 (72.8)||319.1 (118.2)*||236.5 (91.0)|
| Cystometric capacity, mL|| || || |
| Baseline||308.5 (135.0)||250.5 (86.7)||280.2 (100.8)|
| 3 months||388.0 (126.8)*||406.9 (178.6)*||292.0 (99.5)|
| Detrusor pressure, cmH2O|| || || |
| Baseline|| 24.7 (14.9)|| 13.4 (5.74)|| 23.2 (18.3)|
| 3 months|| 18.6 (10.4)*|| 12.7 (6.11)|| 22.7 (16.5)|
| Qmax, mL/s|| || || |
| Baseline|| 14.1 (6.1)|| 10.2 (6.48)|| 13.1 (5.95)|
| 3 months|| 15.1 (4.54)|| 11.5 (7.26)|| 13.6 (5.62)|
| PVR, mL|| || || |
| Baseline|| 30.4 (53.2)|| 13.3 (41.2)|| 38.7 (79.3)|
| 3 months|| 66.7 (106.5)*|| 82.7 (155.6)*|| 30.2 (50.5)|
For the urodynamic variables after treatment there was a significant increase in CBC in the BoNT-A patients (26% in BoNT-A100U, 63% in BoNT-A200U) compared with the HD group (4%, P = 0.007). However, the increases in MBC, CBC or FBC were not significantly different between BoNT-A100U and 200 U groups. Table 2 lists the adverse events in all subgroups. Seven patients in the BoNT-A200U and three in the BoNT-A100U had difficult urination and large PVR in the initial 2 weeks after treatment. All of these patients except for two in the BoNT-A200U group could achieve a balanced bladder at 3 months. Two patients in the BoNT-A200U with chronic urinary retention had a small PVR at 6 months after treatment. The PVR after treatment was significantly greater in the BoNT-A groups compared with the HD group (P = 0.041).
Table 2. Adverse events after treatment in three groups
|N (%):|| || || || || || || |
| BoNT-A200 U||15||2||3||7||5||2||2|
| BoNT-A100 U||29||0||0||3 (10)||2 (7)||1 (3)||0|
| HD||23||0||0||1 (4)||0||0||0|
Figure 1 shows the Kaplan–Meier cumulative survival curves for cumulative success rates of the three groups. The success rate in the BoNT-A200 U, BoNT-A100 U and HD group was 11 of 15, 20 of 29 (69%) and eight of 23 (35%) at 6 months, 11 of 15, 13 of 29 (45%) and six of 23 (26%) at 12 months, respectively. At 18 months, the successful result in the BoNT-A200U, BoNT-A100 U and HD group was sustained by nine of 15, 12 of 29 (41%) and five of 23 (22%) patients and at 24 months by seven, six of 29 (21%) and four of 23 (17%) patients, respectively (P = 0.007). If we combined the results for the two BoNT-A groups, the success rate was also significantly greater in the overall BoNT-A group than in the HD group (P = 0.002).
Figure 1. Comparison of Kaplan–Meier cumulative success rates: A, among all three subgroups; and B, between BoNT-A and HD groups.
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- PATIENTS AND METHODS
- CONFLICT OF INTEREST
The present study showed that intravesical injections of BoNT-A plus HD increased bladder capacity and provided long-term pain relief in patients with IC/PBS and that these effects were superior to those obtained with HD alone. Increasing the dose of BoNT-A from 100 U to 200 U however, did not provide an additive benefit for pain relief or bladder capacity increase. By contrast, the higher dose of BoNT-A was associated with increased incidence of difficult urination and chronic urinary retention, which might be intolerable de novo complaints after BoNT-A treatment.
Currently, there is no satisfactory treatment for bladder hypersensitivity and IC/PBS. Although a leaky urothelium has been speculated to cause chronic inflammation of the bladder, intravesical heparin therapy or oral PPS cannot eradicate the bladder pain and intractable frequency in most patients with IC/PBS [3,19]. These findings suggest that restoration of epithelial function can only partially repair the pathophysiology but not the inflammatory or possible central sensitization pain process that characterizes IC/PBS.
The suburothelial space immediately below the basal lamina is well supplied with sensory nerves, which transmit the sensation of bladder fullness and response to bladder inflammation . These sensory receptors in suburothelial nerve fibres decrease after intradetrusor injections of BoNT-A for human detrusor overactivity . Local inflammatory process might be induced through the afferent and efferent nerves in the suburothelial interstitial cellular network that integrate the transmission of signals from the urothelium to the detrusor muscles in the bladder wall. Inhibition of neuroplasticity of the sensory fibres in the suburothelial space by intravesical BoNT-A injections might have good therapeutic targeting of pain and sensory urgency in patients with IC/PBS .
In the present study, treatment with intravesical BoNT-A injection plus HD might have effects on both detrusor and suburothelial nerves. Bladder stretch increases heparin-binding epidermal growth factor-like growth factor and conversely reduces antiproliferative factor activity in urine from patients with IC/PBS up to 2 weeks after distention . Combined intravesical BoNT-A with HD might yield an additive effect both on pain relief and increased bladder capacity in the present study.
Interestingly, in the present study there was no significant difference between 100 U and 200 U BoNT-A in pain reduction or bladder capacity increase, suggesting that injection of 100 U BoNT-A at 40 sites was sufficient to achieve the optimal effect on the sensory nerves. The increased incidence of difficult urination and chronic urinary retention in patients receiving 200 U BoNT-A was probably caused by a greater depressive effect on detrusor contractility at this dose. Patients who had HD with no BoNT-A injection had a short-term effect at 1 month, but 70% of them had symptom relapse after the initial period.
Previous studies of the effect of BoNT-A treatment on IC/PBS did not have uniform results. Smith et al. reported a 67% success rate with a therapeutic duration of 9 months. Giannantoni et al.[12,15] found 86% of patients with IC/PBS treated with 200 U BoNT-A had improved but the duration was only 3 months, the therapeutic effect decreased to 27% by 5 months and none had a treatment effect at 12 months. Our previous study also found a significant improvement of measured variables in eight of 10 patients at 3 months after treatment but only two reported a satisfactory outcome . In the present study, a higher success rate with a longer therapeutic duration than in previous studies of intravesical BoNT-A injection was obtained by combining BoNT-A injection and HD.
Although bladder pain is the key inclusion criterion of IC/PBS, patients might be bothered more by frequency and nocturia. Some patients may have pain relief but frequency nocturia remains, and others have reversed results after treatment. Therefore, using a GRA may reflect the true therapeutic outcome . The discrepancy between VAS reduction and GRA in the present study might be due to the complex pathophysiology of IC/PBS syndrome.
One important factor for the high success rate in patients with IC/PBS receiving BoNT-A and HD in the present study might have been the combined treatment with baseline PPS. Urothelial dysfunction, suburothelial inflammation and neurogenic inflammation in the detrusor muscle might exist alone or in combination in patients with IC/PBS. Thus, a good therapeutic result in patients with IC/PBS might not be expected with a single therapeutic method such as oral PPS treatment, HD, intravesical resiniferatoxin or BoNT-A injection. Combined several therapeutic methods might improve therapeutic outcome especially in the patients with IC/PBS. The use of PPS in addition to BoNT-A injection plus HD in the present study might have limited our ability to assess the true therapeutic effect of BoNT-A injection plus HD; however, because the control arm used the same medication, the additive effect of medical treatment could be expected to be minimal.
In conclusion, intravesical BoNT-A injection followed by HD produced significantly better clinical results than HD alone in the treatment of IC/PBS. However, patients should be carefully monitored for adverse events such as large PVR and UTI after BoNT-A injection.