ELECTROMOTIVE
DRUG ADMINISTRATION FOR TREATMENT OF THERAPY-REFRACTORY OVERACTIVE BLADDER
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A. GAURUDER-BURMESTER, A. BISKUPSKIE, A. ROSAHL, R. TUNN
German Pelvic Floor Center, Urogynecology Section, St. Hedwig Hospital Berlin, Berlin, Germany
ABSTRACT
Purpose:
Evaluate the benefits of electromotive drug administration (EMDA) as an
alternative technique in patients with chronic overactive bladder in terms
of improvement of symptoms, quality of life, and sexuality.
Material and Methods: A total of 72 patients
with therapy-refractory overactive bladder according to the ICS (International
Continence Society) definition, were treated by EMDA. The regimen consisted
of three treatment cycles, each with 3 instillations at 2-week intervals.
The solution instilled consisted of 100 mL 4% lidocaine, 100 mL distilled
water, 40 mg dexamethasone, and 2 mL epinephrine. Peri-interventionally,
a urine test and close circulatory monitoring were performed. All women
underwent urodynamic testing and cystoscopy and kept a voiding diary.
A comprehensive history was obtained, a quality of life questionnaire
administered, and a gynecologic examination performed before initiation
of therapy. The women underwent follow-up at 12 months after the end of
therapy.
Results: The patients had a mean age of
63 (± 11.2) years. Bladder capacity improved significantly by 109
mL (± 55 mL) in 51 (71%) patients (p = 0.021). The number of micturitions/day
decreased significantly to 7 (± 2) (p = 0.013). Quality of life
was improved in 54 patients (75%); p = 0.024) and sexuality in 39 (54%);
p = 0.020).
Conclusions: The results suggest that EMDA
can improve both quality of life and sexuality in patients with therapy-refractory
chronic overactive bladder.
Key
words: overactive bladder; therapy; quality of life; sexuality
Int Braz J Urol. 2008; 34: 758-64
INTRODUCTION
Overactive
bladder (OAB) has a socioeconomic impact that is comparable to that of
diabetes mellitus. As life expectancy is increasing, this condition will
become even more important in the future. In the new classification of
the International Continence Society (ICS) (1), an overactive bladder
is defined as a complex of symptoms comprising frequency, nocturia, and
sudden compelling desire to void with or without urge incontinence. OAB
has a prevalence of approximately 17%. The etiology of OAB comprises neurogenic
and non-neurogenic detrusor overactivity and detrusor hypersensitivity;
also discussed is urothelial dysfunction (2). Most affected patients seek
medical advice very late, at a time when the symptoms have progressed
to a stage where permanent treatment is required. Compliance is poor in
most patients who have already tried a variety of therapies that failed
or led to minor improvement at best. Most approaches rely on medications.
Comparison of the effects of different agents is difficult because the
reported studies investigating these therapies differed in design and
patients population investigated. Moreover, physiotherapeutic education
and behavioral training or bladder drill are offered either alone or in
combination with medical treatment. After these therapeutic options fail
to cure or improve OAB, physicians and patients are often at a loss. The
cost for incontinence aids increases and many of the patients in whom
all therapeutic options have been tried are on long-term sick leave or
incapable of gainful employment. We therefore intended to offer a treatment
that has previously been established and has been shown to be effective
in patients diagnosed with OAB. Electromotive drug administration (EMDA)
combines iontophoresis and electrophoresis for targeted delivery of drugs
to deep tissue layers. This is achieved by means of an electrical field
created between electrodes. Passive diffusion overcomes some of the limitations
of conventional drug administration and achieves a higher local concentration
of the drug while reducing possible toxic effects. At the same time, EMDA
can be used to improve bladder capacity by means of bladder distension
without the need for anesthesia. Our aim was to establish an effective,
permanent or repeatedly applicable therapy for patients with chronic OAB
while at the same time minimizing adverse effects.
In the study presented here, EMDA therapy
was used in 72 patients with overactive bladder.
Treatment consisted of a stepwise approach.
Patients were initially treated with anticholinergics. If two anticholinergics
failed, patients were treated with uropol-S® instillation. Alternatively,
electrostimulation with a current of 20 Hz or less combined with bladder
training was offered. If this also failed, patients underwent urodynamic
and cystoscopic diagnostic workup. Patients in whom the diagnosis of OAB
was confirmed were then treated by EMDA. The aim of our study was to show
that EMDA therapy improves the patients’ quality of life and sexuality.
MATERIALS AND METHODS
A
total of 72 patients with therapy-refractory overactive bladder according
to the definition of the ICS (3) received EMDA treatment. Of the 85 patients
initially eligible for the study, 13 (20%) were excluded from treatment
because they had abnormal pelvic floor electromyography (EMG) findings.
Inclusion Criteria: Patients were included
if they had a history of OAB persisting for over 24 months and therapeutic
attempts with at least two different anticholinergic medications and at
least 6 months of physiotherapy without improvement or cure of symptoms:
frequency (voiding more than 8 times a day), nocturia (voiding more than
once a night), and urge incontinence. The voiding frequency was determined
by means of a voiding diary the patients kept for three days. All patients
underwent urodynamic testing before and after treatment. The following
parameters were determined: first urge to urinate (normal: one third of
total bladder capacity), bladder capacity (normal: > 300 mL), and positive
detrusor contractions. Presence of residual urine was an exclusion criterion.
Residual urine was determined by ultrasound and clinically by means of
catheterization during urodynamic testing. A cystoscopy was performed
in patients who had their last cystoscopy more than 6 months earlier.
A vaginal examination served to rule out
pelvic organ prolapse and to evaluate the mucosa (4). Introital ultrasound
was performed in a standardized manner (5) and served to verify abnormal
findings (e.g., exclusion of urethral diverticula, tumors). Each patient
was administered a quality of life (6) and sexual exploration questionnaire
(7) before and after treatment. Quality of life was assessed using the
validated Kings Health questionnaire. The questionnaire on sexuality was
compiled by the Institute for Sexual Medicine of Humboldt University in
Berlin and is also a validated measuring instrument.
Voiding frequency, nocturia, first urge,
bladder capacity, quality of life, and sexuality were compared before
and after treatment. Pad counts were not done because the results were
not comparable as patients use a diversity of products.
Each patient received three treatment cycles
each with three instillations at two-week intervals (± 3 days).
The solution instilled consisted of 100 mL 4% lidocaine hydrochloride
(NaCl-free), 100 mL distilled water, 40 mg dexamethasone sodium phosphate,
and 2 mL epinephrine. Close circulatory monitoring was performed peri-interventionally
(6 times a day) and a urine test was done. Patients were hospitalized
for three days.
The EMDA system used in the study consists
of a control unit (Physionizer® 30, UROMED) and a catheter electrode
with a diameter of 16F and a shaft length of 40 cm. The electrode (CE-DAS®
UROGENICS® /Ag 9701) was inserted and then blocked by means of a balloon
inflated with 3 mL of air. The bladder was rinsed with distilled, sterile
water and drained. Bladder tolerance was then determined as the level
at which symptoms occurred. The medications instilled had a total volume
that was 5-10 mL below the bladder capacity at which the individual patient
experienced symptoms. Two patch electrodes were applied to the abdomen
and the Physionizer® was connected to the catheter and the patch electrodes.
Patients were treated for 20-25 min with application of 15-25 mA. Current
was increased at a rate of 30-60 uA/sec. The frequency was 2.5 kHz. The
current applied was direct current with rectangular impulses. Absolute
contraindications were urinary tract infection before therapy, allergy/intolerance
of local anesthetics, massive intravesical bleeding, pregnancy, patients
taking medications of the group of monoaminoxidase inhibitors and cardiac
pacemaker.
Patients underwent follow-up 12 months after
the last treatment.
Statistical analysis was performed by the
Institute of Dr. Matthias Koch-Moeck using MedCalc 9.0.
RESULTS
History
and Diseases
The patients had a mean age of 63 (±
11.2) years. With a Body Mass Index of 31 (± 4.1), the majority
of patients were overweight. Overweight
was found to correlate with the symptoms of OAB.
Fifteen patients (21%) had a history of
anti-incontinence surgery and 19 (27%) had undergone prolapse surgery.
There was no correlation with OAB. Five patients were nulliparae. The
number of deliveries in the other patients ranged from 1 to 7. The number
of deliveries had no effect on the severity of symptoms. Eighteen patients
with type II diabetes mellitus (25 %) had no EMG changes of the pelvic
floor. Twelve patients (17%) had neurological disorders that did not correlate
with their urogynecologic diseases (Figures-1 and 2).
Eighteen patients (25%) were previously
treated by electrostimulation, 46 (64%) by a combination of electrostimulation
and biofeedback (Table-1).
Clinical
Examination
Pelvic floor muscle contraction was assessed
using the Oxford grading system (8). The average strength was 2 (±
2) and an association was found between poor strength and premature first
urge (p = 0.0003).
The gynecologic examination did not show
any prolapse in any of the patients (ICS stage 0). Fifty-one (71%) patients
had a pH of 4.2 (± 0.2), indicating good estrogenization, while
21 (29 %) had poor estrogenization with a pH of 5.5 (± 0.1). The
patients with poor estrogenization were prescribed ovestin ovula pessaries
(for vaginal application every 3 days for 3 months). Introital ultrasound
did not show any significant pathology.
Urodynamic
Testing
The average bladder capacity was 185 mL
(± 32 mL) and patients had an average voiding frequency of 16 (±
3) times a day. In 33 patients, bladder capacity was significantly improved
by 110 mL (± 25 mL) (p = 0.0001). Voiding frequency decreased significantly
to 7 (± 2) times a day (p = 0.003). Nineteen patients (26 %) had
detrusor overactivity, which was terminal in 15 of them (21 %) and phasic
in the other 4 patients (30.8%). In 7 (37%) of the 19 (26%) patients,
it was not possible to evaluate involuntary detrusor contraction following
treatment. The first urge was premature in 41 (57%) patients before treatment
versus 18 (25%) after treatment (Tables-2 and 3).
No abnormal residual urine volumes were
identified either sonographically or clinically.
Nocturia,
Quality of Life, and Sexuality
Nocturia showed a tendency to improve from
5 (± 2) to 2 (± 1).
Quality of life was improved in 54 patients
(75%); patients (p = 0.002). Thirty-nine (54%) patients had improved sexuality
(p = 0.001) in terms of sexual sensations and sexual satisfaction. Quality
of life was unchanged in 15 (21%) and worsened in three (4%), Figure-3.
Adverse
Effects
Twelve of the women (17%) developed reactive
hypertension during treatment, which returned to normal without intervention.
Signs of dysuria and hematuria were observed
in a total of 21 patients (29%). Urinary tract infection occurred in 10
women (14%) and was treated with a 7-day regimen of 250 mg ciprofloxacin
(2 x 1 tablet), followed by a urine test. One patient developed urinary
retention, which disappeared after she was catheterized twice.
COMMENTS
Although
the number of patients investigated in our study is still too small to
draw any general conclusions, our data clearly suggests that the symptoms
of overactive bladder tend to markedly improve using electromotive drug
administration (EMDA) for treatment. Our therapeutic approach cannot be
compared with other currently available treatments using agents such as
oxybutynin, protamine sulfate, and dimethyl sulfoxide (9,10) because these
procedures use very different modes of administration.
The combination of drugs we used was specifically
selected to control urge and pain as well as chronic inflammation of bladder
tissue, which is present in most affected patients. The approach used
here allows simultaneous bladder distension for improving bladder capacity
without the need for anesthesia. We attribute the improvement observed
in our patients to the drugs administered by iontophoresis (EMDA) and
bladder distension since they did not receive additional anticholinergic
treatment or physical therapy. From a strictly scientific point of view,
our study population should have been compared with a control group receiving
placebo. Ethical considerations precluded this approach because most of
our patients had very long histories of chronic disease. Investigation
of a larger group of patients might provide sufficient evidence for the
effectiveness of EMDA. Both above-mentioned effects of this therapeutic
approach were observed in our patients: voiding frequency was reduced
in our patients while bladder capacity was markedly increased. These effects
in turn improved quality of life in general as well as sexuality (less
involuntary urine loss during and around intercourse, greater enjoyment
of sexual sensations, more frequent orgasms). We also found that an abnormally
high BMI tended to impair pelvic floor function, suggesting that affected
patients should be helped to lose weight by means of dietary therapy adapted
for this population. Analysis of the medications and physiotherapeutic
approaches used in the patients before EMDA treatment revealed no association
with outcome. However, a slightly improved response rate was seen in the
patients who were treated with oxybutynin transdermal patches (kentera®)
but the difference was not significant. The adverse effects seen in our
patients were moderate and comparable to those reported in the literature
(11). However, the circulatory effects associated with this kind of treatment
suggest that closer cardiologic workup should be performed prior to treatment.
The current pre-therapeutic diagnostic workup has already been supplemented
by an ECG and a medical consultation. Circulatory monitoring is needed
in all cases. Quality of life was unchanged in 15 (21%) and worsened in
three (4%).
Three patients (4%) who did not report improvement
had poor compliance in that the treatment sessions were performed at very
irregular intervals. We assume that this reduced the efficiency of EMDA
but have no definitive evidence because the time differences were too
small (± 3 days).
OAB is not a normal condition in adults
regardless of age, sex, and degree of mobility. While not life-threatening,
the condition is associated with an unnecessary economic burden and may
lead to isolation, depression, embarrassment, and low self-esteem of affected
individuals. The results presented here suggest that very good outcome
can be achieved with EMDA, which allows local drug administration without
severe adverse effects. Our results deserve to be further corroborated
in larger studies investigating EMDA as second-line treatment option in
patients with overactive bladder, since we observed an improved quality
of life during one-year follow-up. Therefore, we think it is very promising
to continue treatment, assess intermediate-term results, and adjust the
therapeutic approach as needed.
CONFLICT OF INTEREST
None declared.
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____________________
Accepted after revision:
July 22, 2008
________________________
Correspondence address:
Dr. Annett Gauruder-Burmester
Deutsches Beckenbodenzentrum
Grobe Hamburger Str. 5-11
Berlin, 10115, Germany
Fax: + 030 2311-2728
E-mail: a.gauruder@googlemail.com