REVIEW
Management of
overactive bladder
Maya Basu
Abstract
Overactive bladder is a common and bothersome condition which has
a major and measurable impact on sufferers’ quality of life. The cardi-
nal symptom of urgency, with or without urgency incontinence, fre-
quency and nocturia is thought to be caused by abnormalities in
detrusor smooth muscle function and/or sensory pathways. A struc-
tured assessment approach is of importance, including a detailed his-
tory of symptoms, medical and drug history and lifestyle factors such
as fluid intake. Conservative management revolves around the key
principles of fluid modification, avoidance of potential triggers and
bladder retraining. Pharmacological options include antimuscarinic
and beta agonist drugs. These medications have proven efficacy but
compliance varies due to side effects and poor tolerability. Anti-
cholinergic burden is an important factor to consider in prescribing
to older women taking concurrent medications. If conservative and
medical therapy is ineffective, further options include intra-detrusor
botulinum toxin injections and neuromodulation.
Keywords detrusor overactivity; overactive bladder; urgency; urinary
incontinence
Overactive bladder (OAB) is one of the most common chronic
healthcare problems affecting women. Although it is not a life
threatening condition, it can severely affect quality of life. The
treatment and containment of the symptoms of OAB such as
incontinence causes a considerable socio-economic burden for
sufferers, their caregivers and society as a whole.
Definitions and epidemiology
The International Continence Society (ICS) defines the Over-
active Bladder Syndrome as “Urgency, with or without urgency
incontinence, usually with frequency and nocturia”. This defi-
nition is only applicable in the absence of infection or any other
proven pathology. It is important to note that this is a symptom
based diagnosis, which is not dependent on urodynamically
proven detrusor overactivity.
Whilst many studies have attempted to elucidate the preva-
lence of OAB, the true number of women living with these
symptoms is difficult to define. A population study across six
European countries (France, Germany, Italy, Spain, Sweden and
the UK) estimated that 16.6% of the population aged over 40
years had OAB symptoms; this was estimated to equate to 22.2
million individuals with OAB in these six countries. The EPIC
study estimated the prevalence of OAB across five Western
countries (the UK, Germany, Canada, Sweden and Germany); it
Maya Basu BSc (Hons) MRCOG MD Consultant Urogynaecologist, St
Mary’s Hospital, Manchester, UK. Conflicts of interest: none
declared.
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reported the prevalence of OAB across these countries to be
11.8%. A projection using UN population statistics estimated an
increase to 25.5 million people by the year 2020, with nine
million suffering from urgency incontinence.
The symptom of urgency (defined as a compelling need to
urinate which is difficult to defer) is the key feature of OAB. It is
important to distinguish pathological urgency from the normal
bladder sensation of urge e the key distinguishing feature is the
ability to defer the void. By definition, urgency will result in
increased frequency of micturition since the void cannot be de-
ferred. Assuming that fluid intake remains constant, this reduced
inter-void interval will lead to a lower volume voided per
micturition, i.e. lower functional bladder capacity.
The pathophysiology of urgency and overactive bladder
The overactive bladder exhibits a characteristic set of signs:
 A sudden increase in intravesical pressure at low volumes
during filling
 Increased spontaneous myogenic activity
 Fused tetanic contractions
 Altered responsiveness to stimuli
 Changes in smooth muscle ultrastructure
Abnormal detrusor contractions may arise either due to mal-
function of the detrusor muscle itself (myogenic theory), mal-
function of the neural input into the detrusor or malfunction of
sensory output from the bladder. It is likely that OAB in different
patients has different aetiologies.
Assessment
A careful history of the symptoms experienced by the patient as
well as other screening questions for bladder dysfunction, such
as the presence of stress incontinence, symptoms of prolapse,
recurrent urinary tract infection, should be taken. Constipation is
a major contributory factor to OAB, so a bowel history should be
taken. Relevant medical complaints and a drug history will help
to evaluate for other contributory causes. An enquiry about fluid
intake will assist in advising on fluid modification. Examination
should aim to exclude pelvic masses and evaluate for urogenital
atrophy, which should be treated if seen.
OAB is a symptom based diagnosis, therefore the only
essential baseline investigations are those needed to exclude
other pathology. In practice, this means that all women pre-
senting with urgency, urgency incontinence, frequency and/or
nocturia should have a urinalysis to exclude urinary tract infec-
tion. Women who are at higher risk of voiding dysfunction (i.e.
older women or those with symptoms suggestive of voiding
dysfunction) should have a post-void residual measured either
using a bladder scanner or using an ineout catheter.
A voiding diary is typically done over 3 days and allows
quantification of the nature and volume of fluid ingested, as well
as the frequency of voids, the volume voided and recording of
incontinence and urgency episodes. The voiding diary is an
essential tool in the evaluation of women with OAB since it will
allow the clinician to assess whether or not a patient has an
appropriate fluid intake and will also permit assessment of a
patient’s functional bladder capacity. Voiding diaries can also be
used to assess response to treatment and to facilitate bladder
retraining.
1 Ó 2019 Published by Elsevier Ltd.
 REVIEW
Urodynamics permit an objective assessment of lower urinary
tract function and can be used to verify the presence of detrusor
overactivity (DO) (involuntary detrusor contractions during
filling, which may be spontaneous or provoked). Repeated
studies have shown a poor correlation between OAB and the
presence of DO on urodynamics, and treatment response is not
dependent on the presence of DO, therefore urodynamics are not
indicated as a first line investigation unless other pathology is
expected. In patients with refractory symptoms, many clinicians
will undertake urodynamics, however studies of patients un-
dergoing second line treatments for OAB have also indicated that
this does not affect treatment outcome.
Cystoscopy is not a routine first line investigation for patients
with OAB. This would only be undertaken if there was a suspi-
cion of other pathology, e.g. haematuria.
Treatment principles in women with OAB
The principles of treatment of a woman presenting with urgency
and/or urgency incontinence are based on the basic escalating
measures of conservative, medical and interventional. A greater
understanding of the role of detrusor contractions and sensory
disturbance in the disease process, as well as increasing avail-
ability of urodynamic studies, has lead to a treatment model
based on lifestyle modifications and behavioural measures, in
combination with pharmacotherapy, which aims to modulate the
detrusor muscle and urothelial activity.
Conservative measures and behavioural therapy
Women with urgency symptoms and/or detrusor overactivity are
thought to benefit from simple advice regarding fluid intake,
avoidance of caffeine and weight loss (if applicable). However,
the evidence base for this in the literature is limited when
compared to that which exists for other therapies.
There is expert consensus that modifying fluid intake is of
benefit in patients with OAB. Caffeinated and carbonated drinks
are particularly likely to contribute to OAB symptoms. A reduc-
tion in daily fluid intake of 25% is associated with a significant
improvement in OAB symptoms. Caffeine intake has been shown
to be associated with a lower threshold for bladder sensation and
a lower bladder capacity during filling cystometry when
compared to water.
Bladder retraining involves gradually increasing intervals
between voiding in the hope of rediscovering central control of
continence using an operant learning model. This allows higher
centres in the brain to suppress the dominant stimuli which
precipitate detrusor contraction via a voluntary pathway. Patient
education on fluid intake and monitoring with regular bladder
diaries are an intrinsic part of the process. A systematic review
undertaken in 2004 reviewed data from five trials with a total of
467 women. The evidence showed no significant benefit for
bladder retraining when compared to no treatment. When added
to other treatments, e.g. physiotherapy, bladder retraining was
associated with a significant benefit in the short term which was
not sustained at 3 months’ follow up. Evidence does suggest
however that the addition of bladder retraining to pharmaco-
therapy has significant benefits in terms of efficacy. In-patient
bladder retraining and antimuscarinic therapy for patients with
symptoms refractory to out-patient management shows
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significant symptom improvements. Outpatient instruction on
bladder retraining is more usual, and has been suggested to lead
to significant reductions in incontinence episodes; however,
compliance may be suboptimal outside of a trial setting.
Pelvic floor muscle training (PFMT) has long been regarded as
an effective adjunct in the treatment of stress incontinence, but is
less commonly used in urgency and urgency incontinence. There
is very little in the literature to support its effectiveness. In-
struction on pelvic floor contraction to manage urgency episodes
and prolong voiding intervals is likely to be of some use as part of
a bladder retraining programme, but this has not been subject to
evaluation in the literature.
Pharmacotherapy
The basis of most drug treatments for OAB is blockade of
muscarinic stimulation to the detrusor muscle. The detrusor
muscle is supplied by the parasympathetic nerves via spinal
segments S2, S3 and S4. The micturition reflex is activated by
myelinated Ad fibres which lead to an increase in efferent
outflow resulting in detrusor contraction. The predominant
neurotransmitter at the nerve endings on the detrusor muscle is
acetylcholine acting via muscarinic M3 receptors. Blocking of
these receptors leading to a reduction in detrusor overactivity is
the classical concept that underpins antimuscarinic pharmaco-
therapy for DO. There is now increasing evidence that anti-
muscarinic drugs may also have sensory mediated effects via the
urothelial pathways, and that muscarinic receptor function in
women with OAB may be distinct from that in those without
OAB.
The adrenergic beta 3 receptor is also of importance in the
pathophysiology of OAB. Beta 3 adrenoreceptors are highly
expressed in the bladder, particularly in the detrusor muscle and
urothelium. Beta 3 adrenoreceptor agonists have been found to
act on motor function during the storage phase to reduce detru-
sor muscle tone, with animal studies demonstrating suppression
of induced detrusor contractions during the filling phase 3 and
detrusor muscle relaxation. There is also some evidence that beta
3 adrenoreceptor agonists have an effect on sensory signalling in
the bladder.
Antimuscarinics are the recommended first line medical
treatment for OAB symptoms. The choice of drug is a balance
between clinical efficacy and adverse effects.
Oxybutynin
Oxybutynin is a tertiary amine which has anticholinergic effects
on smooth muscle, including the bladder. It was the first anti-
cholinergic drug that was used for overactive bladder symptoms,
although a number of newer drugs have been developed over
recent years. Oxybutynin has muscle relaxant and local anaes-
thetic effects in addition to an anti-muscarinic action. It is se-
lective for M1 and M3 receptors over M2 receptors. Oxybutynin
is available in immediate release (IR), once daily extended
release (ER) and transdermal formulations. Randomized control
trials have shown oxybutynin IR to be superior to placebo in
terms of reduction of voiding episodes and incontinence epi-
sodes, however in normal clinical practice, the marked adverse
effects, particularly dry mouth, are frequently dose limiting, and
only a minority of patients are able to persist with treatment
beyond 6 months. In addition, IR oxybutynin has a well
2 Ó 2019 Published by Elsevier Ltd.
 REVIEW
established effect on cognition and has been shown to lead to an
increase in falls in older patients. For this reason, it should not be
used in older women.
These difficulties highlighted a need for modified formulations
and drug delivery systems to overcome these side effects. There
are no significant differences in efficacy between IR and ER
oxybutynin, however the ER formulation is better tolerated with
a lower incidence of dry mouth. Transdermal forms of drug de-
livery using topical patch formulations of oxybutynin have been
developed to further overcome adverse effects caused by hepatic
metabolites which have been shown to be most associated with
dry mouth. Several large controlled studies have shown trans-
dermal oxybutynin to be effective in managing OAB symptoms,
but with a decreased incidence of adverse effects such as dry
mouth.
Tolterodine
Tolterodine was launched in 1998 in an attempt to introduce a
drug with higher bladder selectivity, and thus fewer anti-
muscarinic side effects. Evidence from large trials suggests that
tolterodine is as effective as oxybutynin, but with a lower inci-
dence of dry mouth. As with oxybutynin, both twice daily im-
mediate release (IR) and a once daily extended release (ER)
formulations are available, with the extended release formula-
tions being better tolerated.
Fesoterodine
Fesoterodine is a pro-drug of tolterodine, which has been
developed in response to the need for formulation of tolterodine
with flexible dosing capability. Fesoterodine is rapidly hydro-
lysed by non-specific ubiquitous esterases to 5-hydroxymethyl
tolterodine, which is the active metabolite of tolterodine. Feso-
terodine can be administered in two doses, 4 mg and 8 mg.
Pharmacokinetic studies have shown that plasma concentrations
are dose proportional. Fesoterodine has been shown to be
significantly more effective than placebo in terms of urgency
episodes, incontinence episodes and quality of life. The benefits
of fesoterodine above placebo have been shown to be dose
dependent. Open label extensions of 12 week RCTs have shown
sustained improvements in health related quality of life and OAB
symptoms at 12 and 24 months.
Trospium chloride
Trospium is a quaternary amine with predominantly peripheral
antimuscarinic activity, leading to smooth muscle relaxation in
the bladder. It is thought to lack the potential for cognitive side
effects since it is unable to cross the blood brain barrier, and so
has particularly been advocated for use in the elderly. As with
other antimuscarinics, it is available in immediate and extended
release formulations. Several phase 3 trials have shown trospium
to be effective in reducing urgency and incontinence episodes,
with measurable improvements in bladder diary variables across
all age groups.
Solifenacin
Solifenacin is a phenylethylamine derivative and was developed
as an M3 selective antimuscarinic. Phase 3 trials have found
solifenacin to be significantly superior to placebo in terms of
incontinence episode reduction and urgency symptoms. A long
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term open label study which was an extension of 2 phase 3
studies showed that 81% of participants were willing to continue
with solifenacin over a treatment period of 40 weeks. Other
studies have also identified positive long term effects on quality
of life. Published data indicates that solifenacin is also effective in
patients with mixed incontinence. A subgroup analysis of sub-
jects with mixed urinary incontinence from four phase 3 RCTs of
solifenacin found significant improvements in urgency and in-
continence episodes, micturition frequency and voided volume
both in subjects with mixed incontinence and urgency inconti-
nence above placebo. The reduction in total incontinence epi-
sodes suggests that the increase in voided volume did not lead to
a worsening of the stress urinary incontinence symptom
component.
Darifenacin
Darifenacin is a tertiary amine derivative and is another M3 se-
lective muscarinic receptor antagonist. It is known to have a
higher degree of selectivity for the M3 over the M2 receptor when
compared to other anticholinergics, with some selectivity for the
M1 receptor. A pooled analysis of Phase 3 studies showed
Darifenacin to have significant, dose dependent positive effects
on urgency symptoms, incontinence and bladder capacity. The
most common side effects were dry mouth and constipation,
although these lead to few discontinuations. There were no
cardiovascular or cognitive side effects associated with darife-
nacin treatment. A 2 year open label study showed that this
favourable efficacy and safety profile was maintained over a
longer treatment period.
Mirabegron
Mirabegron is a more recent addition to the treatment algorithm
for OAB. It is the first commercially produced beta 3 adrenor-
eceptor agonist licensed for the treatment of women with OAB
symptoms. Several phase 3 trials have found mirabegron to be
associated with a significant reduction in incontinence episodes,
micturition frequency and urgency episodes. A meta-analysis of
several RCTs of mirabegron versus solifenacin showed it to have
equal efficacy but with a significantly lower incidence of anti-
muscarinic side effects.
Mirabegron can also be combined with antimuscarinics. A
study evaluating the effect of treatment with a combination of
solifenacin and mirabegron reported combination therapy to
have a significantly higher efficacy when compared to either drug
alone or placebo with only a marginal increase in dry mouth and
no excess in cardiovascular side effects.
Adverse effects of drug treatment
As mentioned previously, treatment with antimuscarinics is often
associated with high discontinuation rates due to poor tolera-
bility. Antimuscarinic side effects are caused by blockade of
muscarinic receptors at sites outside the bladder, such as the
salivary glands (causing dry mouth), the brain (causing impaired
cognition and somnolence) and the gastro-intestinal tract
(causing acid reflux and constipation). Of these side effects, the
most significant from both a safety and patient point of view is
cognitive impairment.
3 Ó 2019 Published by Elsevier Ltd.
 REVIEW
The concept of anticholinergic burden (ACB) has been under
increasing focus over recent years. As well as antimuscarinics
used for OAB, many common drugs such as thyroxine and
prednisolone have anticholinergic activity. In older patients who
may be taking a number of different medications with anticho-
linergic activity, there is evidence that the summative effect of
these medications may lead to a significant and clinically
measurable decline in cognitive function, particularly in those
who already have cognitive impairment. For this reason anti-
muscarinics should be avoided in elderly patients with cognitive
impairment, and caution should be exercised in those who are on
other drugs with cholinergic activity. Oxybutynin is contra-
indicated in elderly women with other comorbidities.
Mirabegron does not have any activity at muscarinic receptors
therefore it is not associated with the side effects discussed
above. Beta 3 receptors are found widely in the cardiovascular
system, therefore theoretically potential side effects will be car-
diovascular in nature. However, a pooled analysis of cardiovas-
cular events and changes in blood pressure from patients across
multiple studies show no difference between mirabegron and
placebo.
Choice of drug treatment
There have been a number of head to head trials and network
meta-analyses evaluating the efficacy of difference drugs for
OAB. In terms of efficacy the drugs discussed here have similar
success rates. Discontinuation rates however have been shown
to be lower with mirabegron due to its favourable side effect
profile. In practice, the choice of drug will be a balance between
previous treatments, relevant medical history and tolerability.
Non-drug therapies for OAB
Conservative management and pharmacotherapy remain the
mainstay of treatment for OAB symptoms. However, there is a
subset of patients with more intractable symptoms, who fail to
respond to multiple therapies. For these patients, other, more
invasive, treatments have been developed.
Botulinum neurotoxin type A (BoNT-A)
This is a neurotoxin produced by the bacterium Clostridium
botulinum and is one of the most poisonous substances known to
man. It is known to bind to peripheral cholinergic terminals and
inhibit acetylcholine release at the neuromuscular junction by
irreversibly cleaving the SNAP-25 protein. The clinical effects of
treatment with BoNT-A will therefore persist until regrowth of
new motor endplates has occurred-this will typically be a few
months, and is the reason why the effect of BoNT-A wears off
over time. Seven distinct botulinum toxins (A-G) have been
isolated, but it is botulinum toxin A that is of most interest to the
medical community.
BoNT-A is injected cystoscopically into the detrusor muscle at
multiple sites. Although initial studies described sparing the
trigone due to the risk of vesico-ureteric reflux, randomized ev-
idence now suggests that including the trigone is associated with
higher efficacy and no significant difference in voiding dysfunc-
tion or reflux (
BoNT-A is indicated in the management of women with OAB
symptoms refractory to medical therapy, or who cannot tolerate
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medical therapy. The first RCT evaluating BoNT-A was published
in 2007 and included 34 patients with idiopathic DO who were
randomized to receive onaBoNT-A or placebo. BoNT-A admin-
istration was associated with a significant increase in maximum
cystometric capacity, and a decrease in micturition frequency
and urgency incontinence episodes, with these benefits persisting
at 24 weeks post-injection. Another study of 240 women ran-
domized to 200u onaBoNT-A or placebo with a 6 month follow
up found a more than 50% reduction in urgency and urgency
incontinence in the BoNT-A group and a 30% continence rate
versus a 12% continence rate in the placebo group. A dose
finding study identified 100u of onaBoNT-A as the dose which
balances efficacy with the risk of adverse effects such as voiding
dysfunction.
The effect of BoNT-A injections is not permanent, meaning
that repeated treatments may be necessary. An open label
extension of a large multicentre RCT demonstrated that repeated
BoNT-A injections have a consistent and repeatable duration of
action and efficacy.
Evidence suggests that the benefits of BoNT-A are seen in
women with OAB symptoms, regardless of whether or not
detrusor overactivity has been seen on urodynamics.
Urinary retention requiring catheterization is the most
commonly described side effect following BoNT-A administra-
tion, and many clinicians will therefore teach patients clean
intermittent self-catheterisation prior to treatment. RCTs have
described BoNT-A related rates of ISC to be between 7 and 20%.
Use of BoNT-A in neurogenic DO patients has been associated
with muscle weakness, but this has not been described in idio-
pathic patients.
Neuromodulation
Neuromodulation is an increasingly popular treatment option for
women with refractory OAB symptoms. The concept is based on
stimulation of pelvic nerves in order to decrease uninhibited
detrusor contractions. Various animal studies have demonstrated
that stimulation of the pudendal nerve or sacral nerve roots de-
creases detrusor contractions during filling. Human studies have
confirmed that sensory input via the pudendal nerve inhibits DO.
Stimulation of afferent nerves is thought to increase the inhibi-
tory stimuli to the efferent nerves, leading to a decrease in
contractility. The two types of neuromodulation in common use
in urogynaecological practice are percutaneous posterior tibial
nerve stimulation (PTNS) and sacral nerve stimulation (SNS)
PTNS has the advantage that it is a minimally invasive and
office based treatment. It involves the placement of a small
needle over the medial malleolus in order to electrically stimulate
the posterior tibial nerve. The end result is stimulation of the S3
spinal cord root via the peroneal nerve. Initial small studies
showed a 50% cure or improvement rate with few complications.
There have subsequently been several RCTs evaluating out-
comes. The SUmiT trial evaluated PTNS against sham therapy in
220 adults with OAB symptoms, and reported a 54.5% cure/
improvement rate with PTNS versus 20.9% with sham, and no
serious adverse events. An RCT of PTNS versus tolterodine
showed an 80% subjective cure or improvement rate with PTNS
versus 54.8% with tolterodine, with similar objective outcomes.
A potential problem with PTNS is a drop off in efficacy following
the initial 12 week treatment period. Transcutaneous tibial nerve
4 Ó 2019 Published by Elsevier Ltd.
 REVIEW

stimulation works via an adhesive patch applied over the pos-

terior tibial nerve, i.e. without the use of a needle, and it there-
fore is suitable for home use. A small study of the use of
transcutaneous tibial nerve stimulation in women who had
positively responded to a 12 week course of PTNS showed that
this was effective in the maintenance of symptom improvement
and so may overcome the potential issue of a lack of long term
efficacy with PTNS by allowing women to “top up” at home.
SNS involves implantation of a pulse generator which stim-
ulates the S3 nerve roots. It is a two stage process. Stage 1 in-
volves an initial screening test in order to identify patients who
will have an adequate response to treatment. This consists of
placement of a temporary lead (either a unilateral tined lead, or
bilateral percutaneous leads), often under fluoroscopic guidance,
which is then connected to an external stimulator. The initial
screening test lasts for 7 days, during which a minimum 50%
improvement in bladder diary variables will be deemed adequate
to justify progression to stage 2. This consists of insertion of an
implantable pulse generator (IPG), which is tunnelled and
implanted under the skin and connected to the S3 nerve root
unilaterally via a tined lead.
A recent systematic review of the available evidence evalu-
ating SNS for urgency incontinence described an improvement of
>50% in between 29 and 76% of subjects. Overall continence
rates ranged from 43 to 56%. The most common adverse events
are pain and trauma at the IPG site, infection, haematoma and
lead migration. A 5 year follow up of patients with an IPG after a
successful stage 1 showed a gradual decline in efficacy, with 87%
success at 1 month to 62% at 5 years. The overall evidence
suggest that success rates seem to be good, and it is an acceptable
option for women with refractory symptoms.
Surgery
Surgical options for urgency symptoms are highly specialized
and include augmentation (clam) cystoplasty and urethral
diversion procedures. These surgical procedures carry a high
Practice Points
C OAB is a common and debilitating condition with a significant
socioeconomic burden. Management requires a multidisciplinary
approach, with conservative measures such as bladder retraining
and fluid modification being an important adjunct to
pharmacotherapy.
C Pharmacotherapy is characterized by high discontinuation rates
due to adverse effects or lack of efficacy, although newer treat-
ments such as beta 3 adrenergic receptor agonists are better
tolerated
C Cystoscopic injection of botulinum neurotoxin A to the detrusor
muscle and neuromodulation are effective treatments for patients
with symptoms refractory to medical therapy
degree of morbidity and should be reserved as options for pa-
tients with severe refractory symptoms. A
FURTHER READING
Allison SJ, Gibson W. Mirabegron, alone and in combination, in the
treatment of overactive bladder: real-world evidence and experi-
ence. Ther Adv Urol 2018; 10: 411e8.
Flint R, Rantell A, Cardozo L. AbobotulinumtoxinA for the treatment of
overactive bladder. Expert Opin Biol Ther 2018; 18: 1005e13.
Kelleher C, Hakimi Z, Zur R, et al. Efficacy and tolerability of mirabe-
gron compared with antimuscarinic monotherapy or combination
therapies for overactive bladder: a systematic review and network
meta-analysis. Eur Urol 2018; 74: 324e33.
National Institute for Health and Care Excellence. NG123: urinary in-
continence and pelvic organ prolapse in women: management.
NICE, 2019.
Peyronnet B, Mironska E, Chapple C, et al. A comprehensive review of
overactive bladder pathophysiology: on the way to tailored treat-
ment. Eur Urol 2019; 75: 988e1000.

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