Urodynamic effects and safety of modified intravesical oxybutynin chloride in patients with neurogenic detrusor overactivity: 3 years experience
Motoaki Saito md phd, Department of Surgery, Division of Urology, Tottori University Faculty of Medicine, 86 Nishimachi, Yonago, Tottori 683-0826, Japan.
Abstract Background: Intravesical oxybutynin chloride with hydroxypropylcellulose (HPC) (modified intravesical oxybutynin) has been reported to be effective for treatment of overactive bladder. We reported the short-term effects of modified intravesical oxybutynin previously. In the present article, we detail the results of a 3-year follow-up study of patients from our previous analysis and report the efficacy and side-effects of modified intravesical oxybutynin.
Methods: Modified intravesical oxybutynin (5 mg/10 mL, twice a day) was applied for more than 3 years to six neurogenic overactive detrusor patients (three men and three women, average age 53.3 years) who were not satisfied with oral anticholinergic agents or the other therapy. A cystometogram (CMG) was performed before, 1 week after and 3 years after the start of modified intravesical oxybutynin treatment. We evaluated the patient's satisfaction of this treatment after 4 weeks and again after 3 years. We compared the patients’ answers before and after the therapy (excellent, good, fair, unchanged and worse). We also monitored systemic and topical side-effects in these patients during this period.
Results: CMG studies showed that two of six patients no longer exhibited uninhibited contraction 1 week after the treatment and that the cystocapacity of patients before, 1 week after and 3 years after the initial modified intravesical oxybutynin was 129.7 ± 19.4, 283.5 ± 40.4 and 286.8 ± 38.1 mL, respectively. For the evaluation of patients’ satisfaction with this treatment, four patients considered the therapy excellent and one patient described it as good after both 4 weeks and after 3 years. Two patients dropped out of the study; one developed left ureteral cancer (2.25 years) and the other developed ileus (1.5 years). Dry mouth and acute cystitis were observed in both patients.
Conclusion: Modified intravesical oxybutynin is an effective and relatively safe option of therapy for overactive bladder patients. However, this therapy requires careful observation for emergent side-effects.
Treatment with oral anticholinergic drugs is effective for patients with overactive bladder. There are, however, some patients who do not respond to oral medication, or who experience intolerable systemic side-effects from these drugs.1–3 It has been reported that intravesical oxybutynin chloride is an effective therapy against overactive bladder.3–5 However, the effects of intravesical oxybutynin chloride often do not endure. In an attempt to improve this deficiency, ours and one other research group added hydroxypropylcellulose (HPC), a mucosal adhesion substance, to the oxybutynin chloride solution.2,6 Excellent short-term efficacy has been reported for this therapy.2,6 However, there has been no long-term follow up. Herein, we present a 3-year follow-up report on efficacy, safety and side-effects in neurogenic detrusor overactivity treated with modified intravesical oxybutynin.
Patients and methods
The backgrounds of the patients were presented in a previous report (see Table 1).6 Because one patient (initials TH) moved to another hospital and we were unable to follow up, her data were discarded. We also added one spinal cord injury patient (initials SK). Modified intravesical oxybutynin chloride was administrated to six neurogenic detrusor overactive patients (three men and three women) who had presented with urinary frequency and urge incontinence or detrusor overactivity incontinence without sensation at the outpatient clinic of Tottori University Hospital around the time of May 1998. These patients were carefully provided information about the risks and possible side-effects of the treatment before joining the study. Because YD was 14 years old, unconscious and bed-ridden, we carefully provided the information to her parents before starting this study. The patients’ ages ranged from 14 to 74 years. Table 2 shows a list of previous treatments used against detrusor overactivity in these patients. Before therapy with modified intravesical oxybutynin, anticholinergic medication was stopped for 2 weeks. Following this, all patients had to undergo a urodynamic study to verify the diagnosis of neurogenic bladder. Five patients (ST, HA, YD, HH and SK) had been administered clean intermittent self-catheterization (CIC) because of detrusor-sphincter dyssynergia (DSD) and their significant volume of residual urine (>100 mL). One patient (MI) started CIC in order to prepare for this treatment. HA had a complication of Sjogren's syndrome. YD was unconscious and bed-ridden because of brain injury due to a traffic accident. Before modified intravesical oxybutynin treatment, all patients were administered oral anticholinergic medication (oxybutynin chloride or propiverine hydrochloride), which was intended to help diminish side-effects (i.e. dry mouth and constipation).
Table 1. Patient profile
|ST||48||F||Adhesive arachnoiditis/detrusor overactivity + DSD|
|HA||67||M||Behcet's disease/detrusor overactivity + DSD|
|YD||14||F||Brain injury/detrusor overactivity + DSD|
|MI||74||M||Herniated disk/detrusor overactivity|
|HH||65||F||HAM/detrusor overactivity + DSD|
|SK||52||M||Spinal cord injury/detrusor overactivity + DSD|
Table 2. Treatment of patients before intravesical oxybutynin
|ST||Oxy, Prop||9y3m||dry mouth, constipation||ES, RTX|
|HA||Oxy, Prop||8y6m||dry mouth, constipation|| |
|MI||Oxy, Prop||4m||dry mouth|| |
|HH||Oxy, Prop||5y10m||dry mouth, constipation|| |
|SK||Oxy, Prop||3y7m||dry mouth||RTX|
Composition of the oxybutynin solution
The composition of the oxybutynin solution was as follows: oxybutynin chloride 5 mg, sodium chloride 58 mg, hydroxypropylcellulose (HPC) 100 mg, sodium dihydrogenphosphate (anhydrous) 52.6 mg, disodium hydrogenphosphate (anhydrous) 8.7 mg and water 10 mL (pH. 5.85), as explained in our previous report.6
Evaluation of the treatment
The oxybutynin solution was instilled twice daily, via the catheter used for bladder emptying, at a dosage of 5 mg/10 mL. A cystometogram (CMG) was performed before, 1 week after, and 3 years after the first instillation of oxybutynin. We also carefully observed side-effects of the patients during this period. Four weeks and 3 years after the initiation of this therapy, or when the patient dropped this therapy, we asked them to estimate their level of satisfaction with the modified intravesical oxybutynin treatment (excellent, good, fair, unchanged and worse), relative to their condition before the therapy started, as previously reported.6 Data could not be collected for YD. Statistical analyses among groups were performed using analysis of variance and the multiple comparison Fisher's test (statistical level of significance, P < 0.05).
Chemicals and drugs
Oxybutynin chloride and hydroxypropylcellulose were purchased from Sigma Chemical Company (St. Louis, MO). All other chemicals were of reagent grade.
Backgrounds of the patients are shown in Tables 1 and 2. In this study, six neurogenic bladder patients (three males and three females, average age 53.3 years) were given modified intravesical oxybutynin treatment. The CMG data are shown in Table 3. Before the treatment, all patients presented uninhibited contractions (UIC), and bladder capacity was 129.7 ± 19.4 mL. One week after the initial treatment, bladder capacity had significantly increased to 283.5 ± 40.4 mL, and this efficacy was maintained; bladder capacity after three years was 286.8 ± 38.1 mL. Furthermore, UIC was undetectable in two patients (ST and YD) after 1 week.
Table 3. Bladder capacity of the patients before and after modified intravesical oxybutynin
|Mean ± SE||129.7 ± 19.4||283.5 ± 40.4*|| ||286.8 ± 38.1*|| |
The results of our survey of patient satisfaction with the modified intravesical oxybutynin treatment are presented in Table 4. Four patients (ST, HA, HH and SK) characterized the therapy as excellent and one patient (MI) classified it as good. These levels of satisfaction were continued for more than 3 years for these four patients. The evaluation of fair, unchanged and worse was not obtained from these patients at any time during follow up.
Table 4. Satisfaction of modified intravesical oxybutynin
Side-effects experienced by the patients are displayed in Table 5. Two patients dropped out of the study; one because of left ureteral cancer (HA, 2.25 years) and the other because of ileus (YD, 1.5 years). Dry mouth was observed in two patients (HA and MI). Acute cystitis was observed in two patients (ST and HH). No other side-effects (e.g. facial flushing or dizziness) were observed.
Table 5. Side-effects experienced by the patients
|ST||Cystitis (four recurrences per year)|
|HA||Dry mouth (moderate), dropped out because of left ureteral cancer (2 years, 3 months)|
|YD||Ileus, dropped out (1.5 years)|
|MI||Dry mouth (moderate)|
|HH||Cystitis (two recurrences per year)|
Based on data from the present study, although patient numbers are only small, modified intravesical oxybutynin therapy is highly evaluated by patients who do not respond to oral anticholinergic medication.
In the present study we investigated the effects and side-effects of modified intravesical oxybutynin treatment in patients who had experienced more than 3 years of treatment. Although the number of patients in this study was only six, a significant increase in bladder capacity was observed, and this effect was maintained over the 3 year follow-up period. Ileus, dry mouth, and acute cystitis were observed in one, two and two patients, respectively. Our data suggest that modified intravesical oxybutynin is one option in treating overactive bladder patients who do not response to oral anticholinergic agents.
Brendler et al. first reported the efficacy of intravesical oxybutynin chloride, and since then evidence of intravesical oxybutynin's effectiveness has been confirmed.4,5,7 This intravesical oxybutynin therapy is thought to depend on three mechanisms that prevent or improve urge incontinence: a direct effect on the bladder muscle, a topical anesthetic effect, and the indirect effect of absorbed oxybutynin and its metabolites.
Some side-effects of this therapy have been reported. Weese et al. reported that among 42 cases of intravesical oxybutynin treatment, nine patients had difficulty retaining the solution in the bladder.8 Kasabian et al. reported other side-effects of this therapy: among 19 neurogenic bladder patients who were treated, there was one patient with facial flushing, three patients with thirst, one patient with urinary tract infection, and two patients with difficulty retaining the solution in the bladder.9 Based on previous reports, difficulty retaining the solution is the most common side-effect or drawback. In the present study, we attempted to reduce this side-effect, and our results seem to demonstrate our success at this. Palmer et al. reported that facial flushing, dizziness, agoraphobia and hyperactivity are the main side-effects.10 In the present study, we only observed ileus, dry mouth, and acute cystitis over the 3-year period. Patient HA had the complication of Sjogren's syndrome. After dropping out of this therapy, he continued to experience dry mouth without anticholinergic therapy. The patient YD was unconscious and always on the bed because of brain injury due to a traffic accident. Before this therapy, she sometimes had demonstrated ileus due to her status. After dropping out of this therapy, ileus continued without anticholinergic drugs. Therefore, these two side-effects might not be due to modified intravesical oxybutynin but are more likely to have been caused by the patients’ complications. Acute cystitis was observed in two female patients. The ratio of this side-effect might be higher than that of CIC patients without intravesical oxybutynin treatment. Amark et al. reported an increased occurrence of asymptomatic bacteriuria and lower urinary tract infection under intravesical oxybutynin application.11
Data from the present study suggest that the level of patient satisfaction after intravesical oxybutynin treatment is high, and that this satisfaction continues for long periods. Although patients needed intensive medical care after the performance of this therapy, ultimately, this resulted in less side-effects in the long term.
Given the small number of patients and the nature of the present study as a preliminary report, our data only suggest the possibility of one option of treatment for overactive bladder patients. Careful observation is required during this therapy.