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Multiple sclerosis commonly causes urinary frequency, urgency, and urge incontinence resulting from detrusor hyperreflexia. This might be associated with voiding difficulties due to detrusor sphincter dyssynergia. These symptoms can be treated effectively with antimuscarinic drugs (principally oxybutynin) and clean intermittent catheterisation, but the antimuscarinic side effects limit clinical usefulness. Typically these are dry mouth and blurred vision, but include constipation, reflux oesophagitis, and flushing.
Oxybutynin, formulated for intravesical administration, has been reported to be effective for suppressing detrusor hyperreflexia with low incidence of side effects in various neuropathic disorders.1 2 However, this preparation is not widely available.
Atropine is a cheaper, easily obtainable, antimuscarinic drug. Administered intravesically it has been shown to be effective in increasing bladder capacities without side effects in patients with spinal cord injury.3 However, the only study was small and uncontrolled. Whereas the pathologies of multiple sclerosis and spinal cord injury are different, the bladder impairments are similar. This study was designed to investigate the efficacy of intravesical atropine in increasing bladder capacities in patients with multiple sclerosis with detrusor hyperreflexia.
The study received ethics committee approval. Written informed consent was obtained from each patient.
Patients with a definite diagnoses of multiple sclerosis and urodynamically demonstrated detrusor hyperreflexia were recruited into the study. Each was taking oral antimuscarinic medication and using clean intermittent catheterisation. A sample size calculation based on previous data3 identified a target recruitment of 15 patients to achieve a significance level of 0.05 with a power of 0.80 using a crossover study design. Eighteen patients were contacted, of whom 16 consented and 15 completed the study.
Antimuscarinic drugs were stopped 2 days before cystometric testing. Patients attended on two occasions. They were allocated 30 ml of either atropine (6 mg) in normal saline or normal saline only (as placebo). This was done according to random code with both patient and investigator blinded. An independent nurse prepared the solutions.
Standard static saline fill cystometry with a filling rate of 50 ml/min was performed before and 2 hours after intravesical instillation of the test preparations. As this was a first randomised study of a single dose of intravesical drug the outcome measure used was cystometric bladder capacity and not urgency or episodes of urge incontinence. A single prophylactic dose of ciprofloxacin (250 mg) was administered orally on each occasion. At the beginning and end of each cystometric study the patient’s heart rate and blood pressure were measured. All patients were questioned about known antimuscarinic side effects. Blood samples were collected for atropine assays 2 hours after instillation of the test solutions.
Urodynamic data were not normally distributed, therefore non-parametric analysis techniques were used. When comparisons between the difference in change in cystometric bladder capacities were made a Wilcoxon sign ranked test was used quoting the 95% Wilcoxon confidence interval.
The study group consisted of 15 patients (six men and nine women) with a median age of 51 years (range 39–73 years). All patients retained their test solutions after each instillation. The results are shown in table 1. After atropine the bladder volumes increased by a median value of 93 ml (95% confidence interval 45.0–170 (p=0.001)). After saline the cystometric bladder capacity did not change significantly.
No significant changes were found in blood pressures or pulse rates. No side effects were reported by any patient. Atropine was not detected in blood samples 2 hours after intravesical instillation (limit of detection 0.05 mg/l).
This early study provides evidence in favour of the efficacy of intravesical atropine in increasing the cystometric bladder capacity in patients with multiple sclerosis. Cystometric bladder capacity was chosen as an outcome measure because it has been shown to be sensitive to the influence of orally administered antimuscarinic drugs used for the treatment of detrusor hyperreflexia in multiple sclerosis.4 It is therefore likely that urgency and urge incontinence will be improved with the administration of intravesical atropine. However, this will require testing in a randomised controlled therapeutic trial.
The patients did not identify any side effects during the 2 hours after the administration of the atropine. It has been shown that orally administered oxybutynin will induce antimuscarinic side effects in a similar period.5
The absence of measurable drug in the blood at the time of the clinical effect is encouraging. The results show promise and if clinical efficacy were demonstrated this approach would be a useful addition to the therapeutic options for urinary incontinence in multiple sclerosis.
The study was funded by the MS trust fund of the Central Middlesex Hospital London. We thank Professor Stephen Senn of the Department of Epidemiology and Public Health at University College London for statistical advice.
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