BJOG: an International Journal of Obstetrics and Gynaecology
March 2004, Vol. 111, pp. 249 –257
DOI: 1 0 . 1 1 1 1 / j . 1 4 7 1 - 0 5 2 8 . 2 0 0 4 . 0 0 0 6 7 . x
Duloxetine versus placebo in the treatment of European and
Canadian women with stress urinary incontinence
Philip van Kerrebroecka, Paul Abramsb, Rainer Langec, Mark Slackd,
Jean-Jacques Wyndaelee, Ilker Yalcinf, Richard C. Bumpf,*,
for the Duloxetine Urinary Incontinence Study Group
Objective To assess the efficacy and safety of duloxetine in women with stress urinary incontinence.
Design Randomised double-blind, placebo-controlled clinical trial.
Setting Fort-six centres in seven European countries and Canada.
Population Four hundred and ninety-four women aged 24– 83 years identified as having predominant
symptoms of stress urinary incontinence using a clinical algorithm that was 100% predictive of urodynamic
stress urinary incontinence in a subgroup of 34 women.
Methods The case definition included a predominant symptom of stress urinary incontinence with a weekly
incontinence episode frequency 7, the absence of predominant symptoms of urge incontinence, normal
diurnal and nocturnal frequencies, a bladder capacity 400 mL and both a positive cough stress test and
positive stress pad test. Subjects completed two urinary diaries prior to randomisation and three diaries
during the active treatment phase of the study, each completed during the week prior to monthly visits.
Subjects also completed quality of life questionnaires at each visit. Safety was assessed by the evaluation of
treatment-emergent adverse events, discontinuation of treatment because of adverse events, serious adverse
events, vital sign measurements, electrocardiograms (ECG) and clinical laboratory tests.
Intervention After a two-week placebo lead-in, women received placebo or duloxetine 40 mg BD for
12 weeks.
Main outcome measures The percentage decrease in incontinence episode frequency and the change in the
Incontinence Quality of Life (I-QOL) questionnaire total score were prespecified as co-primary outcome
variables in the protocol.
Results Incontinence episode frequency decreased significantly with duloxetine compared with placebo
(median decrease of 50% vs 29%; P = 0.002) with comparable improvements in the more severely
incontinent subgroup (those experiencing at least 14 incontinence episodes per week at baseline; 56% vs
27% decreases; P < 0.001). The primary analysis of I-QOL scores did not reveal a significant difference
between treatment groups, due primarily to the carrying forward of low scores from patients who
discontinued treatment very early due to duloxetine-associated adverse events. The increase in I-QOL scores
was significantly greater for duloxetine than for placebo at each of the three postrandomisation visits after 4,
8, and 12 weeks of treatment. Discontinuation rates for adverse events were higher for duloxetine (22% vs
5%; P < 0.001) with nausea being the most common reason for discontinuation (5.3%). Nausea tended to be
mild to moderate, not progressive, and transient.
Conclusions The findings support duloxetine as a potential treatment for women with stress urinary
incontinence.
a
INTRODUCTION
* Correspondence: Dr R. C. Bump, Eli Lilly and Company Corporate
Center, Indianapolis, Indiana 46285, USA.
Stress urinary incontinence is defined by the International Continence Society as the complaint of involuntary
leakage of urine on effort or exertion, or on sneezing or
coughing.1 It occurs because a positive urethral pressure
gradient over bladder pressure cannot be maintained during
abrupt increases in abdominal pressure. Stress urinary
incontinence is the most common type of urinary incontinence in women, with 78% of women presenting with the
symptom of stress urinary incontinence in either pure
(49%) or mixed (29%) forms.2 Using year 2000 population
Department of Urology, University Hospital Maastrecht,
Netherlands
b
Bristol Urological Institute, Southmead Hospital, UK
c
Department of Gynaecology, DRK-Krankenhaus, Alzey,
Germany
d
Hinchingbrooke & Addenbrooke’s Hospitals, Cambridge,
UK
e
Department of Urology, University of Antwerp, Belgium
f
Lilly Research Laboratories, Indianapolis, Indiana, USA
D RCOG 2004 BJOG: an International Journal of Obstetrics and Gynaecology
www.blackwellpublishing.com/bjog
250
P. VAN KERREBROECK ET AL.
figures, approximately 18 million women over the age of
20 years have the symptom of pure stress urinary incontinence while 29 million have stress urinary incontinence in
pure or mixed forms in the eight countries that were
included in the current study. Based on data showing that
stress urinary incontinence is bothersome and severe in
17% to 24% of incontinent women,3 it can be calculated
that between three and seven million of these women have
severe or bothersome stress urinary incontinence.
Currently, the most accepted forms of therapy for female
stress urinary incontinence are pelvic floor muscle training,
various types of behavioural interventions and continence
surgery. Only a small minority of women with bothersome
stress urinary incontinence undergo continence surgery. For
example, in the United States only 130,000 did so in 1997,4
fewer than 5% of American women with bothersome stress
urinary incontinence. An undetermined number of women
with stress urinary incontinence use various forms of pelvic
floor muscle training in an attempt to improve their
continence, however, they often fail to comply with a
pelvic floor muscle training program both acutely and
chronically. In one study, the majority of women (61%)
prescribed pelvic floor muscle training for stress urinary
incontinence were not compliant; 15% trained only once
weekly, 3% once monthly and 43% not at all.5 There are
currently no data to explain this relatively poor compliance,
however, it is possible that some women are discouraged by
the relatively slow response with pelvic floor muscle
training and thus fail to dedicate the 15 –20 weeks recommended to determine their response.6 There is currently no
globally approved pharmacological agent for the treatment
of women with stress urinary incontinence.
Numerous animal studies have implicated serotonin
(5-HT) and norepinephrine in the neural control of lower
urinary tract function. In non-rodent species, serotonergic
agonists suppress parasympathetic activity and enhance
sympathetic and somatic activity in the lower urinary
tract,7 – 9 effects that promote urine storage by relaxing
the bladder and increasing outlet resistance. Noradrenergic
agonists and antagonists variably affect sympathetic and
somatic activity in the lower urinary tract, depending on the
adrenergic receptor subtype with which they interact.10 – 15
Duloxetine hydrochloride is a balanced and potent inhibitor of serotonin and norepinephrine reuptake, and is
being developed for the treatment both of stress urinary
incontinence and of major depression. Preclinical pharmacological data demonstrate a superiority of duloxetine with
respect to its relative affinity in binding to the norepinephrine and serotonin transport sites compared with venlafaxine, the only available selective dual reuptake inhibitor.16
Based upon the continence-promoting properties of
serotonin and norepinephrine, animal studies were conducted with duloxetine to determine its effects on lower
urinary tract function. Duloxetine significantly increased
bladder capacity and sphincteric muscle activity in the cat
acetic acid bladder model, effects that were reversed by the
nonselective serotonergic antagonist methiothepin and by
prazosin and LY53857, alpha-1 adrenergic and 5-HT2 serotonergic receptor antagonists, respectively.17 It has further
been demonstrated that the storage-promoting effects of
duloxetine on the lower urinary tract are unique to dual
serotonin and norepinephrine reuptake inhibition in a single
molecule, and are not duplicated by the administration of
single reuptake inhibitors alone or in combination.18
Duloxetine’s ability to increase rhabdosphincter contractility via stimulation of pudendal motor neuron alpha-1
adrenergic and 5-HT2 receptors, is believed to be the underlying mechanism responsible for its efficacy in women with
stress urinary incontinence reported recently from a phase
two randomised controlled trial.19 This manuscript reports
the results from a phase three trial performed in Western
Europe and Canada. The aim of this study was to further
characterise the efficacy and tolerability of duloxetine
hydrochloride as a potential pharmacological treatment
for female stress urinary incontinence.
METHODS
Women aged 18 years and older with a clinical diagnosis
of bothersome stress urinary incontinence of at least three
months duration were invited to participate in this doubleblind, placebo-controlled, randomised clinical trial conducted at 46 study centres in Belgium, Canada, Denmark,
France, Germany, the Netherlands, Sweden and the United
Kingdom. The institutional review board for each site
approved the study and written informed consent was
obtained from all participants. To enrol, women must have
reported a predominant symptom of stress urinary incontinence with seven or more incontinence episodes per week,
a diurnal urinary frequency of less than eight per day, a
nocturnal urinary frequency of two or less per day and the
absence of predominant symptoms of urge incontinence.
All patients underwent a supine bladder infusion. Those
who were unable to tolerate the filling to 400 mL or who
experienced a first sensation of bladder filling <100 mL
were excluded. After bladder filling, both a positive cough
stress test and a positive stress pad test were required for
inclusion. This clinical algorithm has been demonstrated
to predict urodynamic stress incontinence with an accuracy of 92%.19 In the current study, a subset of 34 patients
had filling phase multichannel cystometry at five centres,
all of whom had urodynamic stress incontinence confirmed according to International Continence Society
standards.1
After a two-week screening period and a two-week nodrug lead-in period followed by a two-week single-blind,
placebo lead-in period, patients were randomised under
double-blind conditions to 12 weeks of treatment with
duloxetine 40 mg BD or placebo (Fig. 1). All patients
received two identical capsules twice daily and were seen
at four-week intervals throughout the treatment period.
D RCOG 2004 Br J Obstet Gynaecol 111, pp. 249 – 257
DULOXETINE TREATMENT OF STRESS URINARY INCONTINENCE
251
Fig. 1. Study design and the timing of acquisition of urinary diary and quality of life measurements reported.
Patients were randomised using a computerised voiceresponse system at a central location. A stratified randomisation using baseline incontinence episode frequency (<14
or 14 episodes/week) was performed to prevent potential
imbalance in incontinence severity. Treatment assignments
were also balanced at each investigative site.
The percent change in incontinence episode frequency
from baseline to endpoint (calculated from patient completed daily paper diaries) was one of the two prespecified
primary outcome variables. The daily diaries were also
used to collect the number of voids, the time of voids and
the time study medication was taken. Two diaries were
completed prior to randomisation, one during the second
week of the no-drug lead-in and one during the second
week of the blinded placebo lead-in. Three diaries were
completed during the active treatment phase of the study,
each completed during the week prior to the three monthly
visits. Figure 1 provides an overview of the study design
and the timing of acquisition of diaries and other variables.
The second prespecified primary outcome measure of
efficacy was the change from baseline to endpoint in the
total score from the Incontinence Quality of Life (I-QOL)
questionnaire.20,21 This validated, disease-specific, 22-item
instrument was collected at each visit (Fig. 1) and evaluates
the effects of urinary incontinence in three domains (avoidance and limiting behaviour, social embarrassment and
psychosocial impact). The I-QOL includes questions that
evaluate both the distress and impact of urinary incontinence with a score of 100 being the best possible and zero
being the worst possible quality of life. It is one of the two
quality-of-life instruments that received the World Health
Organization’s Second International Consultation on Incontinence highest (‘highly recommended’) rating for conD RCOG 2004 Br J Obstet Gynaecol 111, pp. 249 – 257
dition-specific measures of incontinence impact in men and
women.22
Another validated quality-of-life measure, the Patient
Global Impression of Improvement (PGI-I) rating was
obtained at each postrandomisation visit and served as a
prespecified secondary efficacy outcome variable. It is a
single question, measuring patient’s self-perceived improvement in her urinary tract condition since she started
treatment.23 Finally, the validated Patient Global Impression
of Severity (PGI-S) scale23 was completed only at baseline.
All efficacy variables were analysed according to the
intention-to-treat principle using data from all randomised
subjects with at least one postrandomisation outcome
measure. Prematurely discontinuing subjects had their last
outcome measure carried forward only in the intention-totreat primary analysis. This analysis is the basis for all
principal efficacy conclusions. No efficacy outcome data
were collected after discontinuation for these subjects.
Because subjects who discontinued the trial prematurely
may have experienced changes in incontinence and quality
of life that could bias the results, efficacy was also evaluated by visit.
Safety was assessed by the evaluation of treatmentemergent adverse events, discontinuation of treatment because of adverse events, serious adverse events, vital sign
measurements, electrocardiograms and clinical laboratory
tests. Adverse events were elicited during an interview
using nonprobing inquiry at each visit and were recorded
regardless of perceived causality. An event was considered
treatment-emergent if it occurred for the first time or
worsened during the double-blind treatment period. A
serious adverse event was defined according to the International Consultation on Harmonization guidelines and
252
P. VAN KERREBROECK ET AL.
included any adverse associated with death, a threat to life,
hospitalisation, a severe or permanent disability, a congenital anomaly or a newly diagnosed cancer or was considered significant for another reason by the investigator.
Patient compliance with the protocol was assessed at
each visit by counting unused medication and by monitoring patient diaries.
The statistical analysis plan was specified a priori. The
percent decrease in incontinence episode frequency was
compared between duloxetine and placebo groups using
van Elteren’s test24 (a type of stratified Wilcoxon test) with
baseline incontinence severity as the stratification variable.
Percent change in incontinence episode frequency is
reported as a median because a few extreme outliers
(placebo þ729%, duloxetine þ2300%) substantially distorted the means. Mean changes in I-QOL scores were
analysed using an ANCOVA model. The dependent variable was the change in I-QOL score and the model included
terms for baseline scores, treatment, site and baseline
incontinence severity strata. The same ANCOVA model
was used to analyse changes in mean voiding intervals.
Categorical variables were analysed by using Pearson’s m2
test or Fisher’s exact test. Mean population differences for
laboratory, vital sign and electrocardiogram data were
analysed using ANOVA. These continuous data were also
assessed for clinically important outliers using prespecified
definitions.
Enrolment into the study was set to end when approximately 440 patients (220 per treatment group) had been
assigned to a treatment group. The sample size was determined to provide at least 80% power to detect a treatment
difference of 20% in the median percent change in incontinence episode frequency and of 3.5 points in the mean
change in I-QOL total score at a 0.05 Type I error level.
These assumptions were based upon observations from the
phase two trial19 and from the minimum important I-QOL
difference reported by Patrick et al.21
Analyses were performed using SAS software, version
8.1 (SAS Institute, Cary, North Carolina). A two-sided
alpha level of 0.05 was considered statistically significant
for treatment effects.
RESULTS
Four hundred and ninety-four women aged 24 to 83
years were randomised to receive duloxetine (247) or
placebo (247) between December 2000 and January 2002.
Most patients (92%) completed at least one postrandomisation diary (86% duloxetine, 98% placebo), while 98%
completed at least one I-QOL questionnaire (97% duloxetine, 99% placebo) and were included in the primary
analysis. In the placebo group, 92% of patients completed
the 12-week study compared with 73% of those in the
duloxetine group ( P < 0.001); the difference was attributable to a higher discontinuation rate related to side effects
Fig. 2. Flow diagram of the study. *Numbers in the diagram differ from
those in Tables 2 and 3 because some patients discontinuing at a visit still
completed diaries and I-QOL questionnaires. The ‘other’ category includes
investigator decision, patient decision and lost to follow up.
in the duloxetine group. Figure 2 summarises the flow of
patients through the study.
On average, patients in the placebo group took 94% of
their treatment doses compared with 82% of doses in the
duloxetine group ( P < .001). This difference in compliance
was attributable to limited duloxetine consumption by
subjects who discontinued from the trial early and was
not significant after the first postrandomisation visit.
Table 1 presents baseline demographic and incontinence
data. Of the baseline variables, only age differed significantly between the treatment groups with the placebo group
being an average two years older than the duloxetine group.
Overall, approximately two-thirds of the study population
considered their urinary tract function to be moderately or
severely abnormal and half averaged two or more incontinence episodes every day.
The decrease in incontinence episode frequency was
significantly greater in the duloxetine group than in the
placebo group both in the primary analysis and in the byvisit analysis (Table 2). Women who had more severe
incontinence (those with 14 or more incontinence episodes
per week) had a response similar to the entire study
D RCOG 2004 Br J Obstet Gynaecol 111, pp. 249 – 257
DULOXETINE TREATMENT OF STRESS URINARY INCONTINENCE
253
a
Table 1. Baseline clinical characteristics of illness severity for all randomised patients. Data are mean (SD) unless otherwise indicated; BMI ¼ body mass
index; PFMT ¼ pelvic floor muscle training; IEF ¼ incontinence episode frequency; I-QOL ¼ Incontinence Quality of Life Questionnaire; PGI-S ¼ Patient
Global Impression of Severity question.
Duloxetine
b
247
244
52
28
19
46
17.3
152
66.7
166
125
Randomised N
Caucasian
Age, yearsc
BMI, kg/m2
Prior continence surgery
Perform PFMT
IEF per week (SD) [range]
Voiding interval, minutes
I-QOL score
Moderate or severely abnormal urinary tract function by PGI-S
14 or more IEF per week
(99%)
(11)
(6)
(7.7%)
(18.8%)
(12.9) [0 – 81]
(39)
(20.1)
(69.5%)
(50.6%)
Placebo
247
241
54
27
19
48
17.2
153
64.5
169
131
(98%)
(10)
(5)
(7.7%)
(19.4%)
(12.4) [1 – 68]
(39)
(21.3)
(71.0%)
(53.0%)
a
Baseline is the last nonmissing visit score on or prior to randomisation.
Every randomised subject did not provide information for each variable; percentages are calculated using the number of responding patients as the
denominator.
c
P ¼ 0.01.
b
population (a 55.9% median reduction in incontinence
episodes with duloxetine compared with a 26.8% reduction
with placebo, P < 0.001).
Over half (51.9%) of the women in the duloxetine group
had a 50% to 100% decrease in their incontinence episode frequency compared with 33.5% of those in the placebo group ( P < 0.001). The superior improvements with
duloxetine were observed at the first postrandomisation
assessment visit (four weeks) and persisted throughout
the 12-week double-blind treatment period (Table 2). In
addition, patients in the duloxetine group also increased
their average voiding interval significantly compared with
those in the placebo group (15.0 vs 3.8 minutes, respectively; P < 0.001).
Table 2. Incontinence episode frequency: primary analysis and by-visit results. CI ¼ confidence interval; IEF ¼ Incontinence episode frequency.
Treatment group (N)a
Primary analysisf
Placebo (247)
Duloxetine (247)
Data by visitg
Placebo (247)
Duloxetine (247)
Time point
Baseline
Endpoint
Change
Baseline
Endpoint
Change
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
2
3 (randomisation)
4 — 4 weeks
5 — 8 weeks
6 — 12 weeks
2
3 (randomisation)
4 — 4 weeks
5 — 8 weeks
6 — 12 weeks
nb
Median IEF
per week
242
14.0
9.0
3.0
13.0
7.0
6.0
212
247
246
237
230
225
246
245
210
187
176
a
15.9
14.0
11.0
9.0
9.1
15.0
13.0
6.6
7.0
7.0
Median percent
IEF change from baselinec
95% CI for median
percent change in IEFd
29.3
36.8, 20.0
50.0
57.1, 42.9
20.0
29.8
28.6
27.1, 10.9
40.6, 23.8
36.4, 18.4
53.6
53.9
51.8
60.0, 46.9
61.1, 46.2
58.8, 42.9
Pe
0.002
<0.001
<0.001
0.002
N ¼ number randomised.
n ¼ number with diary data available for specified analysis or visit.
c
Approximate 95% confidence interval for the median percent change was obtained using nonparametric methods for order statistics.
d
Baseline is the last nonmissing visit score on or prior to randomization.
e
P values for duloxetine versus placebo obtained from van Elteren’s test for analysis of the percent changes in IEF where the stratification variable was
baseline IEF severity.
f
The prespecified primary analysis was based on the intention-to-treat principle using data from every randomised subject with at least one
postrandomisation measure. Prematurely discontinuing subjects had their last outcome measure carried forward in the primary analysis.
g
Analysis compares subjects who had IEF diary records at both the baseline and the respective postrandomisation visit.
b
D RCOG 2004 Br J Obstet Gynaecol 111, pp. 249 – 257
254
P. VAN KERREBROECK ET AL.
Table 3. Incontinence Quality of Life Questionnaire: primary analysis and by-visit results. CI ¼ confidence interval; I-QOL ¼ Incontinence Quality of Life
Questionnaire.
Treatment group (N)a
Primary analysisf
Placebo (247)
Duloxetine (247)
Data By Visitg
Placebo (247)
Duloxetine (247)
Time point
Baseline
Endpoint
Baseline
Endpoint
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
Visit
2
3 (randomisation)
4 — 4 weeks
5 — 8 weeks
6 — 12 weeks
2
3 (randomisation)
4 — 4 weeks
5 — 8 weeks
6 — 12 weeks
nb
Mean I-QOL
245
64.4
68.5
66.6
72.2
240
245
244
244
233
228
242
245
237
192
178
61.1
64.6
67.6
70.0
69.1
62.9
66.6
72.1
75.8
74.6
Mean change in I-QOL
score from baselinec
95% CI for treatment
difference in I-QOLd
Pe
0.5, 4.1
0.127
0.8, 4.6
1.6, 6.3
1.0, 6.2
0.006
0.001
0.008
4.1
5.5
3.2
5.4
4.3
5.6
8.6
7.3
a
N ¼ number randomised.
n ¼ number with diary data available for specified analysis or visit.
c
95% confidence interval for treatment difference (Dulox 80 mg minus placebo) was obtained by using LSMEANS from the ANCOVA model.
d
Baseline is the last nonmissing visit score on or prior to randomisation.
e
P values for duloxetine versus placebo obtained from the comparison of duloxetine 80 mg group to placebo using Type III Sums of Squares from an
ANCOVA model that includes change in I-QOL as dependent variable and baseline I-QOL score, treatment, severity strata and site as independent variables.
f
The prespecified primary analysis was based on the intention-to-treat principle using data from every randomised subject with at least one
postrandomisation measure. Prematurely discontinuing subjects had their last outcome measure carried forward in the primary analysis.
g
Analysis compares subjects who had I-QOL scores at both the baseline and the respective postrandomisation visit.
b
Changes in the I-QOL scores did not show a significant
difference between duloxetine and placebo in the primary
analysis (Table 3). In contrast, there were significant
differences in these parameters when data were analysed
by visit (Table 3). The differences between the primary and
by-visit analysis for the I-QOL results are largely explained
by the carrying forward of low I-QOL scores from duloxetine subjects who discontinued their medication very early
due to side effects but who still completed their initial fourweek treatment visit I-QOL questionnaire. Of the 53
duloxetine-treated subjects who discontinued at visit 4, 42
(79%) did so due to adverse effects. Discontinuing subjects
took a median of 10 doses of duloxetine (five days of treatment) and most (47 or 89%) completed the visit 4 I-QOL
questionnaire. Their increases in I-QOL scores averaged
only 0.6 points.
The analysis of PGI-I data revealed results similar to
those observed with the I-QOL analysis. Only slightly more
subjects in the duloxetine group than in the placebo group
considered their urinary tract condition to be ‘very much
better, much better, or a little better’ in the intention-to-treat
analysis (duloxetine 56.2%, placebo 48.2%; not significant).
However, significantly more subjects who completed the
12-week PGI-I in the duloxetine group than in the placebo
group considered their urinary tract condition to be improved (duloxetine 64.8%, placebo 48.4%; P ¼ 0.008).
Treatment-emergent adverse events were experienced by
more patients in the duloxetine group compared with the
placebo group (81% vs 64%; P < 0.001). Table 4 lists all
side effects that occurred in at least 5% of patients on
duloxetine or that were significantly more common with
duloxetine. Nausea was the most common side effect with
duloxetine. Most (94%) nausea with duloxetine was
reported within four weeks of the start of therapy, 75%
was mild to moderate in severity at onset, and in no
instance did it increase in severity. The majority (57 of
69; 83%) of patients who developed nausea on duloxetine
completed the study. Of these, 40% reported resolution of
the nausea by one week while 75% reported resolution
within one month. While dry mouth and constipation were
Table 4. Treatment-emergent adverse events occurring in at least 5% of
patients randomised to duloxetine or occurring significantly more often
with duloxetine than with placebo. Values are expressed as n (%).
Duloxetine
Nausea
Dry mouth
Constipation
Fatigue
Insomnia
Dizziness
Headache
Sweating increased
Vomiting
Somnolence
Tremor
69
48
35
34
31
30
24
21
16
10
10
(27.9)
(19.4)
(14.2)
(13.8)
(12.6)
(12.1)
(9.7)
(8.5)
(6.5)
(4.0)
(4.0)
Placebo
16
6
10
11
3
8
19
4
5
(6.5)
(2.4)
(4.0)
(4.5)
(1.2)
(3.2)
(7.7)
(1.6)
(2.0)
0
0
P
<0.001
<0.001
<0.001
<0.001
<0.001
<0.001
0.524
<0.001
0.024
0.002
0.002
D RCOG 2004 Br J Obstet Gynaecol 111, pp. 249 – 257
DULOXETINE TREATMENT OF STRESS URINARY INCONTINENCE
Table 5. Discontinuations for adverse events in 1% or more of patients
randomised to duloxetine. Values are expressed as n (%).
Duloxetine
(N ¼ 247)
For any adverse event
Nausea
Dizziness
Insomnia
Attention disturbance
53
13a
9
5
3
(21.5)
(5.3)
(3.6)
(2.0)
(1.2)
Placebo
(N ¼ 247)
12
2
1
1
1
(4.9)
(0.8)
(0.4)
(0.4)
(0.4)
P
<0.001
0.007
0.02
0.22
0.62
a
One subject discontinued due to nausea that was a pre-existing condition that neither started nor worsened after she started taking duloxetine.
also common side effects, they tended to be mild to
moderate (90% and 86%, respectively) in the majority of
patients and rarely (one and two patients, respectively) led
to discontinuation from the study.
The discontinuation rate due to adverse events was significantly higher for the duloxetine group compared with
the placebo group (21.5% vs 4.9%; P < .001). Table 5 lists
all adverse events that resulted in a 1% or higher discontinuation rate for duloxetine.
There was a significant increase in mean heart rate
during treatment with duloxetine compared with placebo;
however, the less than three beats per minute increase with
duloxetine was within the normal range. In addition, outlier
analysis confirmed that there were no clinically relevant
effects of duloxetine on heart rate. There were no significant differences in the mean change for systolic or diastolic blood pressure between the duloxetine and placebo
groups. Three patients (two placebo, one duloxetine) developed sustained hypertension (systolic or diastolic blood
pressure of at least 140 or 90, respectively, and increased at
least 10 mm from baseline for three consecutive visits). A
comprehensive analysis of corrected QT intervals revealed
no arrhythmogenic tendencies with duloxetine. There were
no deaths in the study. Two placebo-treated subjects and
two duloxetine-treated patients experienced serious adverse
events after randomisation. None resulted in a chronic
sequela.
DISCUSSION
In this study, duloxetine was noted to be significantly
more effective than placebo in women with stress urinary
incontinence across the spectrum of stress urinary incontinence severity. With patients averaging two to three incontinence episodes per day and some patients having as many
as 10 incontinence episodes per day (Table 1), the study
population included women who would be traditionally
considered candidates for continence surgery.
A 50% to 100% reduction in incontinence episodes was
seen in more than half of women treated with duloxetine.
This effect was noted within the first four weeks of
treatment and persisted through the three-month study,
D RCOG 2004 Br J Obstet Gynaecol 111, pp. 249 – 257
255
indicating a prompt and durable response. The reduction
in incontinence episode frequency with duloxetine for the
half of the study population that averaged at least 14
incontinence episodes per week was slightly greater than
the reduction observed for the entire population, whereas
the placebo response was somewhat lower in this more
severe subgroup.
The improvements with duloxetine were observed despite a significant increase in the average voiding interval
for duloxetine compared with placebo. Less frequent voiding indicates that the improvements with duloxetine were
not the result of emptying the bladder more often, a
modification of behaviour that can result from the completion of diaries in the clinical trial setting.
These significant improvements in incontinence were
not reflected by improvements in quality of life as measured with the I-QOL and PGI-I instruments in the primary
analysis. These findings contrast with those of the phase
two study in the United States,19 a large phase three study
in the United States and Canada25 and another phase three
study conducted in Europe, South Africa, South America
and Australia26 that together randomised a total of 1419
women with stress urinary incontinence. In each of these
other studies, significant improvements in both quality of
life scales were seen with duloxetine compared with
placebo in the intention-to-treat analysis. In the largest of
these,25 it was demonstrated that these quality of life
improvements resulted from improved stress urinary incontinence and were not the result of the treatment of unrecognised symptoms of depression.
However, quality of life data for patients who completed
this study showed significant improvements with duloxetine compared with placebo. The result is largely explained
by the fact that the results of the intention-to-treat analysis
were influenced by carrying forward the low I-QOL scores
of the duloxetine patients who discontinued very early due
to side effects. The data show that these patients took
medication for a very short period and discontinued before
they had a chance to experience benefit although they still
completed the I-QOL questionnaire.
Significantly more patients experienced treatment-emergent adverse events with duloxetine than with placebo with
22% of duloxetine patients discontinuing therapy due to
side effects. Nausea was the most frequent side effect on
duloxetine with 5.3% of all duloxetine patients leaving the
study due to nausea. Nausea tended to have its onset very
early after starting duloxetine. It was mild or moderate in
most cases, did not worsen after its onset and resolved
within one week to one month of therapy in most cases.
Eighty-three percent of women who experienced duloxetine-related nausea completed the study. Dry mouth and
constipation were not uncommon side effects, however,
these were seldom severe and rarely led to discontinuation
of therapy.
While alpha-adrenergic receptor agonists have been used
for the treatment of stress urinary incontinence, the major
256
P. VAN KERREBROECK ET AL.
concern with these agents is the inability to separate the
peripheral urethral smooth muscle stimulatory effects from
cardiovascular effects in this class of drugs.27 Duloxetine
has a predominant central mode of action through the sacral
cord pudendal motor nucleus to stimulate the urethral
rhabdosphincter17 rather than a peripheral mode of action
on smooth muscle. The slight increase in heart rate with
duloxetine provides evidence for a mild, clinically unimportant peripheral alpha-adrenergic action that was not
associated with any significant change in blood pressure
or clinically important changes in the electrocardiogram.
CONCLUSION
Our data are consistent with published data from North
and South America, Africa and Australia.19,25,26 However,
the improvements with duloxetine must be weighed against
a considerable discontinuation rate due to early side effects.
It is likely that more patients will continue duloxetine in
clinical practice if they are reassured that any early side
effects are unlikely to worsen or persist. Overall, the
efficacy and safety data suggest that an incontinent patient
and her physician should be able to assess the adequacy of
her response by comparing her improvement in incontinence with any persisting side effects after four weeks of
duloxetine treatment.
In summary, these data support duloxetine as a pharmacological treatment for women with stress urinary incontinence, thus increasing the range of options for women with
this problem.
Acknowledgements
The Duloxetine UI Study Group included the following
principal investigators and their staffs; investigators
received funding to conduct this study from the sponsor:
Paul Abrams, FRCS, MD, Southmead Hospital, Bristol,
UK; Karl Moller Bek, PhD, Skejby Sygehus, Aarhus N,
Denmark; BLH Bemelmans, MD, PhD, Radboud Department of Urology, Nijmegen, Netherlands; Steven Bryniak,
MD, St. Joseph Hospital, Saint John, Canada; Hendrik
Cammu, MD, A. Z. – V. U. B., Brussels, Belgium; Pierre
Costa, MD, PhD, Hospital Gaston Doumergue, Nimes
Cedex, France; KPJ Delaere, MD, PhD, Atrium Medisch
Centrum, Heerlen, Netherlands; Marc Dhont, MD, PhD, U.
Z. Gent, Gent, Belgium; David Eiley, MD, Ultra-Med,
Pointe Claire, Canada; Per Ekstrom, MD, PhD, Hospital
Ystads, Ystad, Sweden; Christine Evans, FRCS, MD, Glan
Clwyd Hospital, Denbighshire, UK; Karel Everaert, MD,
PhD, U. Z. Gent, Gent, Belgium; Christian Falconer, MD,
PhD, Danderyds Hospital, Danderyd, Sweden; Aino FianuJonasson, MD, PhD, Huddinge University Hospital, Stockholm, Sweden; Robert Freeman, MD, DM, FRCOG,
Derriford Hospital, Derriford, UK; Francois Haab, MD,
Hospital Tenon, Paris, France; Tahseen Hasan, FRCS,
MD, Freeman Hospital, Newcastle, UK; Lars Henriksson,
MD, University Hospital MAS, Malmö, Sweden; Tim Hillard, DM, FRCOG, Poole Hospital, Poole, UK; Sven Hundertmark, MD, Ausbildungszentrum fuer Frauenheilkunde
Berlin, Berlin, Germany; Udo Jonas, MD, PhD, Medizinische Hochsschule Hannover, Hannover, Germany; Preben
Kjolhede, MD, PhD, University Hospital, Linkoping, Sweden; Kenneth Krohn, Vrinnevijukhuset i Norrkoping, Norrkoping, Sweden; Rainer Lange, MD, DRK-Krankenhaus,
Alzey, Germany; Paula Lowenadler, MD, Trelleborgs
Hospital, Trelleborg, Sweden; Hansjoerg Melchior, MD,
Staedtische Kliniken, Kassel, Germany; Birger Reinhold
Moller, MD, Odense Universitets Hospital, Odense, Denmark; Mahmoud Nachabe, MD, Greenfield Park, Canada;
Ole Nielsen, Grindsted, MD, Denmark; Allan Patrick, MD,
King Tower, Fredericton, Canada; Bo Pettersson, MD,
PhD, Countess Of Chester Hospital, Chester, UK; Jorgen
Praest, MD, Randers Central Sygehus, Randers, Denmark;
Volker Ragosch, MD, Ausbildungszentrum fuer Frauenheilkunde, Berlin, Germany; Olof Rugarn, MD, PhD,
Vrinnevi Hospital, Norrkoping, Sweden; Göran Samsioe,
MD, PhD, Kvinnohalsan, Lund, Sweden; JH Schagen van
Leeuwen, MD, PhD, St Antonius Ziekenhuis, Nieuwegein,
Netherlands; Erik Schick, MD, Maisonneuve Rosemount
Hospital, Montreal, Canada; Mark Slack, MD, Peterborough District Hospital, Peterborough, UK; Torsten
Sorensen, MD, Kolding Sygehus, Kolding, Denmark;
Stuart Stanton, FRCS, FRCOG, St. George Hospital,
London, UK; Tim Terry, FRCS, MS, Leicester General
Hospital, Leicester, UK; PHM van de Weijer, MD, PhD,
Gelre Ziekenhuizen-location Juliana, Apeldoorn, Netherlands; PEV van Kerrebroeck, MD, University Hospital
Maastricht, Maastricht, Netherlands; Kristiaan Vekemans,
MD, Medisch Centrum Practimed, Tessenderlo, Belgium;
HAM Vervest, MD, PhD, St. Elisabeth Ziekenhuis,
Tilburg, Netherlands; ME Vierhout, MD, PhD, University
Hospital Rotterdam, Rotterdam, Netherlands; Jean-Jacques
Wyndaele, MD, DSC, PhD, FEBU, FISCOSU, University
Antwerpen, Edegem, Belgium.
Conflict of interest statement
Dr Yalcin and Dr Bump are both full-time employees of
Eli Lilly and hold stock and stock options in the company.
Dr van Kerrebroeck, Dr Abrams, Dr Lange, Dr Slack and
Dr Wyndaele have served on advisory boards for and have
consulting agreements with Eli Lilly and were investigators
in this study that was funded by Eli Lilly and Boehringer
Ingelheim.
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Accepted 16 October 2003