Treatment of LUTS and OAB
REVIEW ARTICLE
Treatment of Lower Urinary Tract Symptoms and Overactive
Bladder — Focus on Bladder Sensory Innervation
Ding-Yuan Chen, Hann-Chorng Kuo
Department of Urology, Buddhist Tzu Chi General Hospital and Tzu Chi University, Hualien, Taiwan
ABSTRACT
Lower urinary tract symptoms (LUTS) are highly prevalent, especially among elderly men and women, with a negative impact on
health-related quality of life. LUTS are associated with great emotional costs for individuals and substantial economic costs for
society. Recent investigation of LUTS in men noted that bladder dysfunction plays an important role in addition to bladder outlet
obstruction. The urothelial release of neurotransmitters such as acetylcholine (ACh), adenosine triphosphate (ATP) and the neuropeptide substance P, and the expression of TRPV1 and P2X3 receptors strongly imply a role for the urothelium in human bladder
mechanosensation. An abundance of suburothelial sensory nerves and vesicles containing ACh and ATP in nerve fiber terminals
have been found in the human bladder wall, suggesting the lamina propria of the bladder plays an important role in the transmission
of a sensation of bladder fullness and in the bladder response to stretch. In addition, nerve growth factor levels have been shown to
be elevated in the bladder tissues of men with bladder outlet obstruction, patients with overactive bladders, and women with interstitial cystitis. Based on the results from recent investigations, bladder disorders like neurogenic detrusor overactivity, idiopathic
detrusor overactivity, interstitial cystitis, overactive bladder due to bladder outlet obstruction and urothelial dysfunction might have
a common pathway in the abnormality of expression of sensory receptors or release of transmitters in the suburothelial nerves or
interstitial cells. In this regard, inhibition of receptor expression or transmitter release in the sensory nerve terminals in the suburothelial
space might provide good therapeutic effects in the treatment of sensory urgency, interstitial cystitis and detrusor overactivity. (Tzu
Chi Med J 2006; 18:333-344)
Key words: sensory innervation, detrusor overactivity, neurotransmitter, interstitial cystitis, overactive bladder
INTRODUCTION
Lower urinary tract symptoms (LUTS) consist of a
complex of bladder storage and emptying symptoms.
Previously, treatment of LUTS was focused on bladder
emptying symptoms and bladder outlet obstruction
(BOO). Recent investigations have discovered that the
sensory innervation of the urinary bladder plays an important role in storage as well as emptying LUTS. The
treatment strategy for LUTS should be shifted to aim at
the sensory innervation rather than the detrusor muscles.
LOWER URINARY TRACT SYMPTOMS (LUTS)
IN MEN
LUTS are highly prevalent, especially among elderly men and women, with a negative impact on healthrelated quality of life. LUTS are associated with great
emotional costs for individuals and substantial economic
costs for society [1,2]. The prevalence and severity of
LUTS increases with age and the progressive increase
in the ageing population has increased the social economic burden and severity of LUTS [3].
Received: October 6, 2006, Revised: October 13, 2006, Accepted: October 14, 2006
Address reprint requests and correspondence to: Dr. Hann-Chorng Kuo, Department of Urology, Buddhist Tzu Chi General
Hospital, 707, Section 3, Chung Yang Road, Hualien, Taiwan
Tzu Chi Med J 2006 18 No. 5
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D. Y. Chen, H. C. Kuo
LUTS are comprised of storage symptoms (including frequency, urgency, nocturia, and incontinence),
voiding symptoms (including hesitancy, intermittency,
residual urine sensation, straining to void and poor
stream) and postvoid symptoms (incomplete emptying
and terminal dribbling). The pathophysiology of LUTS
could be bladder dysfunction (bladder hypersensitivity,
detrusor overactivity (DO), detrusor underactivity), BOO
(bladder neck dysfunction, prostatic obstruction, urethral
stricture, poorly relaxed urethral sphincter, urethral
sphincter dyssynergia) or a combination of these etiologies [4]. Many men have both storage and voiding
symptoms. In men voiding symptoms are more common,
but storage symptoms are encountered frequently [5].
The frequent co-morbidity with prostatic diseases in men
adds complexity to the diagnosis and management of
male LUTS.
Recent investigations of male LUTS noted that bladder dysfunction plays an important role, in addition to
BOO. LUTS suggestive of an overactive bladder (OAB)
have been estimated to be present in 16% of people in
Europe and United States [6]. A multinational large scale
study revealed that 90% of men aged 50 to 80 years
suffer from potentially troublesome LUTS and many
men have both storage and voiding symptoms [3]. Benign prostatic hyperplasia (BPH) is often associated with
male LUTS, but LUTS cannot be used to make a definite diagnosis of BPH. LUTS can occur in women,
children, and also in men with either poor detrusor function or BOO. OAB symptoms comprise the same symptoms as storage LUTS and their prevalence increases
with age. Since most men with OAB do not experience
incontinence [7], men with storage LUTS are often misdiagnosed with clinical BPH. Storage symptoms correlate poorly with BOO, male OAB symptoms may be
caused by bladder dysfunction such as DO or impaired
detrusor contractility, or occur in combination with BOO
[4]. BOO may cause DO, however, many studies have
reported only 45%-50% of men with LUTS have
urodynamically confirmed DO and BOO [8,9].
LUTS IN WOMEN
LUTS are more prevalent in women than in men.
The influence of ageing, menopause and childbirth add
complexity to the etiology of female LUTS. OAB symptoms are frequently mixed with stress urinary
incontinence. The ageing process results in intrinsic urethral sphincteric deficiency which increases the prevalence of urinary incontinence and may potentiate DO
and OAB symptoms. In Taiwan, about 10% of men and
PPQ
women have symptoms suggestive of OAB [10]. This
figure is far less than that in Europe where 16% of women
were reported to have storage symptoms suggestive of
OAB [6]. In addition to OAB symptoms, women also
have voiding symptoms such as dysuria, intermittency,
residual sensation and urinary retention suggestive of
bladder outlet dysfunction or obstruction. In a large scale
videourodynamic study of women with LUTS, BOO was
found in about 9% of women with LUTS refractory to
medical treatment [11].
OAB symptoms are well correlated with DO,
however, voiding symptoms correlate poorly with BOO.
A study applying the American Urological Association
(AUA) symptom index for LUTS, revealed symptom
scores on the storage and voiding subscales did not differ significantly between men and women from 55-79
years old [12]. In another study from Japan, comparable
storage symptom scores on the International Prostate
Symptom Score (IPSS) were noted in men and women
over 40 years old [13]. In a group of men and women
with persistent storage symptoms, 89% of patients whose
primary symptoms were frequency and urgency had
urodynamic DO [14]. These data suggest that both men
and women have storage and voiding symptoms and can
be assessed with identical symptom score questionnaires
such as the AUA or IPSS symptom indexes.
THE UROTHELIUM AND OVERACTIVE
BLADDER
The urinary bladder urothelium had been viewed as
a passive barrier, however, recent evidences demonstrated that the urothelium is a responsive structure which
exhibits both sensor (ability to respond to thermal, mechanical and chemical stimuli) and transducer (ability
to release chemicals) functions. Studies have also revealed that afferent nerves and urothelial cells in the bladder exhibit a number of common properties, including
the expression of certain receptors and ion channels (such
as TRPV1). In addition, localization of afferent nerves
adjacent to the urothelium suggests that these cells may
be targets for transmitter release from bladder nerves or
that chemicals released by urothelial cells may alter afferent excitability. The alteration in afferent nerves or
urothelial cells in pelvic viscera may contribute to the
sensory abnormalities in the urinary bladder [15].
Recent investigations have shown suburothelial innervation expressing the capsaicin receptor TRPV1 [16],
the purinergic receptor P2X3 [17], and the sensory neuropeptides substance P and calcitonin gene-related peptide (CGRP) [18] in the pathophysiology of human DO.
Tzu Chi Med J 2006 18 No. 5
Treatment of LUTS and OAB
Patients with neurogenic detrusor overactivity (NDO)
due to spinal cord lesions were found to have increased
TRPV1 and P2X3 immunoreactive suburothelial innervation compared to controls [19]. Women with idiopathic
detrusor overactivity (IDO) were found to have increased
density of suburothelial substance P and CGRP immunoreactive fibers compared to controls [18].
The urothelial release of neurotransmitters such as
acetylcholine (ACh), adenosine triphosphate (ATP) and
the neuropeptide substance P, and the expression of
TRPV1 and P2X3 receptors strongly imply a role for the
urothelium in human bladder mechanosensation [20-22].
Recent investigations also discovered a suburothelial
nexus of myofibroblasts or interstitial cells may be the
substrate for a stretch-receptor organ. These cells are
extensively linked by gap junctions and may respond to
ATP in a mode similar to the activation of ATP-gated
P2Y receptors [23,24]. The urothelial release of ACh
and ATP on bladder filling increases with ageing [20]
and in spinal cord NDO [25], implicating an abnormal
release of these neurotransmitters in the pathophysiology of DO. In treatment of IDO with intradetrusor injection of botulinum toxin type A (BTX-A) decreased
immunoreactivity of P2X3 expression in suburothelial
fibers was noted, which correlated with improvement in
patients' sensation of urgency [19].
The actual pathophysiology of detrusor overactivity
after neurogenic lesions, BOO and ageing has not been
well elucidated. Recently, the urothelium and suburothelial space have received renewed interest because of
their possible roles not only in mediating solute transport but also in sensing bladder fullness [26]. An abundance of suburothelial sensory nerves and vesicles containing ACh and ATP in nerve fiber terminals have been
found in the human bladder wall, suggesting the lamina
propria of the bladder plays an important role in the transmission of sensation of bladder fullness and in the bladder response to stretch [27-29]. These stretch-sensing
apparatus may transmit sensory signals as well as mediate the detrusor reflex [30]. A change in hydrostatic pressure on the apical face of the urothelium results in ATP
generation which is postulated to activate P2X3 receptors on sensory nerves [31]. The P2X3 receptors are colocalized with VR-1 receptors and are believed to be
involved in afferent pathways that control urinary bladder volume reflexes [32]. Increased stretch activated ATP
release has been reported from human urothelial cells
cultured from the bladders of patients with interstitial
cystitis and spinal cord injury.
In the mammalian bladder, unmyelinated sensory
afferent C-fibers become predominant and mediate detrusor reflex after spinal cord transection [33]. Intravesi-
Tzu Chi Med J 2006 18 No. 5
cal vanilloid therapy using capsaicin or resiniferatoxin
acts on the vanilloid receptor TRPV1 and is an effective
therapy in patients with detrusor hyperreflexia due to
spinal cord lesions [34]. TRPV1 receptors are found on
the afferent nerves in the lamina propria and co-localize
with acetylcholine- containing nerve fibers as well as
substance P and CGRP in rat bladders [23,26,35].
Under some pathological conditions in the urinary
bladder, such as infection or trauma, the production of
transmitters such as ATP, substance P, and CGRP can
act on nearby tissues and on afferent nerve terminals in
an autocrine fashion to increase afferent nerve activity
[36]. The production and release of these neurotransmitters increase during conditions of inflammation and
pain [37,38]. The suburothelial interstitial cells may be
affected and sensory transmission occurs earlier, increasing the sensation of bladder fullness or mediating detrusor contraction through a gap junction extending into
the detrusor muscles [39,40]. Moreover, many C fibers
in the bladder mucosa contain sensory neuropeptides
(such as substance P, neurokinin A, CGRP) which on
release, can modulate the micturition reflex and might
cause detrusor overactivity [25]. A local inflammatory
process might be induced through the afferent and efferent nerves in these interstitial cellular networks which
integrate signal transmission from the urothelium to
detrusor muscles in the bladder wall [41].
In the urinary tract, nerve growth factor (NGF) is
produced by bladder smooth muscle and urothelium.
Recent work indicates that NGF is involved in the ongoing regulation of neural function, as well as in inflammation and pain. Clinical and experimental data also link
increased levels of NGF in the bladder tissue and urine
to painful inflammatory conditions in the lower urinary
tract, such as interstitial cystitis and chronic prostatitis
[42-44]. Bladder inflammation by intravesical irritants
or in chronic interstitial cystitis leads to acute afferent
nerve activity [45] and to long-term plasticity that lowers the threshold for nociceptive and mechanoceptive
afferent fibers [46]. Chronic sensitization of afferent fibers might involve both peripheral and central
mechanisms. Intravesical irritants cause increased expression of the c-fos protein in the lumbosacral spinal
cord [47]. A rise in bladder NGF in the muscle or
urothelium initiates signals that are transported along
bladder afferent nerves to the dorsal root ganglion or
spinal cord [48]. NGF levels are elevated in the bladders of men with BOO, patients with OAB and women
with interstitial cystitis [48,49]. Intravesical BTX-A reduces levels of NGF in the bladder of IDO as well as
NDO [50]. Although the mechanism for the reduced
bladder NGF has not been elucidated, prevention of neu-
PPR
D. Y. Chen, H. C. Kuo
ral plasticity by blockade of NGF production has been
postulated to cause reduction of urge incontinence and
symptoms of OAB [50].
Based on the results from recent investigations, bladder disorders such as NDO, IDO, OAB due to BOO,
interstitial cystitis and urothelial dysfunction might have
a common pathway in the abnormality of expression of
sensory receptors or release of transmitters in the
suburothelial nerves or interstitial cells [41]. In this
regard, inhibition of receptor expression or transmitter
release in the sensory nerve terminals in the suburothelial
space might provide good therapeutic effects in the treatment of sensory urgency, interstitial cystitis and DO. If
these hypotheses can be proven, patients with DO, bladder hypersensitivity, and interstitial cystitis refractory
to conventional treatment can be treated in a totally new
way without adverse effects. The underlying pathophysiology mediating detrusor hyperreflexia and urgency
frequency as well as bladder pain in DO, OAB, and interstitial cystitis can also be explored.
TREATMENT OF OAB BY INTRAVESICAL
RESINIFERATOXIN
OAB is a symptom syndrome characterized by urgency frequency with or without urge incontinence and
it may affect quality of life [51]. OAB is diagnosed by
subjective symptoms, of which the core symptom is
urgency. Both sensory urgency and DO might be involved in the pathophysiology of this symptom
syndrome. This condition may wax and wane and is
occasionally associated with symptoms of suprapubic
pain with a full bladder. Current treatments are usually
unsuccessful in completely eradicating the urgency
sensation. Behavioral therapy and pelvic floor muscle
training have been tried to relieve this bothersome syndrome [52]. Some patients with OAB and hypersensitive bladder may respond to antimuscarinic agents [53],
but this treatment has some adverse effects such as
dizziness, dry mouth, blurred vision, and constipation,
which are intolerable for some elderly patients [54].
Treatment with intra-detrusor BTX-A injections demonstrated satisfactory results in increasing bladder capacity and decreasing the urgency sensation in patients
with NDO or IDO [55,56]. However, increased postvoid
residual volumes and urinary retention which sometimes
develop in the first post-treatment month may prohibit
its wide-spread application in patients with mild to moderate symptoms refractory to antimuscarinic agents [57].
Therefore, it is mandatory to search for an effective alternative therapy without serious adverse effects that can
PPS
be applied in patients with OAB.
There is not yet a conclusion on the pathophysiology of hypersensitive bladder and OAB. Although
urothelial dysfunction and changes in the urinary potassium concentration have been proposed to account for
this condition, treatments aimed at these pathophysiologies have not been able to improve this condition adequately [58,59]. It is possible that the chronic symptomatology in bladder hypersensitivity is due to central
sensitization and persisting abnormality or activation of
the afferent sensory system [60]. Intradetrusor injection
of BTX-A modulates the release of neurotransmitters
from sensory nerve endings, and effectively modulates
the inflammatory process mediated by nociceptive afferent nerve dysfunction [61,62].
Previous investigations in intravesical vanilloid
therapy were aimed at treating NDO due to spinal cord
lesions [34,63,64]. Only a few investigations have used
capsaicin or resiniferatoxin to treat DO or bladder hypersensitivity from non-spinal cord lesions [65,66]. As
evidenced by positive ice water test results, overexpression and hyperactivity of the vanilloid receptors in the
urinary bladder have been identified in patients with DO
due to various non-spinal lesions [67]. Therefore, use of
intravesical vanilloid agonists such as capsaicin or
resiniferatoxin to treat DO refractory to anticholinergic
agents might be effective.
Intravesical capsaicin therapy exerts an excellent
effect in patients with incontinence due to multiple sclerosis or spinal cord injuries [68-70]. However, because
of its irritative effect, patients with non-spinal lesions
might not be able to tolerate capsaicin therapy.
Resiniferatoxin, an ultrapotent capsaicin analog, has been
shown to have a clinical effect similar to capsaicin but
with less neuronal excitatory effect [71]. Thus, resiniferatoxin treatment is more suitable than capsaicin for patients who have normal bladder sensation and OAB [72].
Resiniferatoxin treatment has been demonstrated to
have a therapeutic effect in patients with detrusor hyperreflexia due to spinal cord lesions [73-75]. At a concentration of 100 nM, resiniferatoxin induced full desensitization and successfully treated detrusor hyperreflexia in neurologically impaired patients who did not
have improvement after capsaicin treatment [75]. In one
study, a 50 nM solution of resiniferatoxin was found to
delay or suppress involuntary detrusor contractions during filling cystometry in patients with IDO [65]. These
findings indicate that desensitization of capsaicin sensitive primary afferents by intravesical resiniferatoxin can
have a therapeutic effect on hyperactive or sensory disorders of the urinary bladder.
The clinical effect of intravesical resiniferatoxin at
Tzu Chi Med J 2006 18 No. 5
Treatment of LUTS and OAB
a concentration of 100 nM was demonstrated in treating
DO due to non-spinal cord lesions in patients refractory
to anticholinergic treatment [76]. Twenty-one of 41 patients with NDO and urinary incontinence had clinical
improvement (51.2%) whereas 18 had stationary results
and 2 developed urinary retention with overflow
incontinence. The effect of resiniferatoxin treatment in
these 21 patients lasted for 2 to 9 months with a median
duration of 5 months. After treatment, the cystometric
capacity significantly increased, and detrusor pressure
showed a significant reduction, but maximal flow rate,
and residual urine volume showed no significant
difference. Among the 20 patients with failed treatment,
only 4 (20%) had an increase in maximal cystometric
capacity by 50% and none had a reduction in detrusor
pressure.
The magnitude of the neurotoxic effect of resiniferatoxin seems to depend on the dose of vanilloids. The
dose that we used in a previous study resulted in temporary neurotoxcity but was insufficient to cause any irreversible effects. Nevertheless, a reduction of detrusor
pressure might account for the decrease in urgency and
urge incontinence in patients with DO. The causes of
failed treatment with resiniferatoxin have not been
elucidated. If complete desensitization of vanilloid receptors accounts for a successful result, then repeat treatment with resiniferatoxin may be helpful in complete
blockage of vanilloid receptors. A high concentration
of resiniferatoxin might cause acute desensitization but
might also result in neurotoxicity to the A-delta fibers
mediating detrusor contractions, whereas a lower concentration might have less neurotoxicity and less desensitization of C-fibers. In order to achieve a better desensitization of C-fibers without neurotoxicity to A-delta
fibers, repeat treatment with a lower concentration of
resiniferatoxin might be necessary.
A recent randomized, double-blind, placebo-controlled study showed that four installations of
resiniferatoxin at a concentration of 10 nM were well
tolerated and effective in about 50% of patients with
refractory detrusor overactivity compared to the control
group at 3 months after instillation [77]. Although the
adverse effects after multiple 10 nM resiniferatoxin treatments were minimal, the therapeutic effect decayed with
time and only 34.6% of the patients exhibited a successful result at 6 months [77]. Thirty four men and 23
women out of a total of 67 patients completed all four
treatments (85%). The success rate in the resiniferatoxin
group was significantly better than in the control group
(78% vs 24%, p<0.001 at one month; 50% vs 14%, p<
0.001 at 3 months; 28.6% vs 3.5%, p<0.001 at 6 months).
At 12 months after treatment only 3 patients (11%) in
Tzu Chi Med J 2006 18 No. 5
the study group and none in placebo group had effective
relief of symptoms (p<0.001). The results of this phase
II study showed that multiple intravesical instillations
of 10 nM resiniferatoxin had a significantly superior
therapeutic outcome compared with a placebo in patients
with refractory DO. The therapeutic results obtained with
multiple instillations of 10 nM resiniferatoxin at 3
months in this study were similar to those in a previously reported study [76].
Resiniferatoxin is a capsaicin analog that is specific
for the vanilloid receptors in the bladder. Vanilloid receptors are present not only on sensory fibers but also in
bladder urothelium and smooth muscle cells [78-80]. The
vanilloid receptor TRPV1 participates in normal bladder function, is essential for normal mechanically evoked
purinergic signaling by the urothelium and is involved
in ATP release [81]. In conditions of NDO and IDO,
there is up-regulation of unmyelinated nerve fibers expressing vanilloid receptors [16]. The vanilloid receptors on the sensory fibers in the bladder become overexpressed in DO, and this is the key for the successful
treatment with resiniferatoxin. In patients with spinal
cord injury, vanilloid-sensitive fibers in the bladder assume a central role in the reflex emptying of the bladder
at low volumes [82]. Instillation of resiniferatoxin can
desensitize vanilloid receptors on the sensitive fibers
resulting in the disappearance of spontaneous detrusor
contractions during bladder filling [65].
Purinergic P2X3-immunoreactive nerve fibers in
NDO were decreased in patients who responded to intravesical resiniferatoxin [83]. Previous study showed
that instillation of 50 nM resiniferatoxin can delay or
suppress involuntary detrusor contractions during filling cystometry, hence, explaining the mechanism by
which urinary incontinence can disappear or improve
after resiniferatoxin treatment [84]. This finding indicates that vanilloid-sensitive fiber input has an important role in the generation of involuntary detrusor contractions in patients with NDO or IDO [75]. Although
intravesical resiniferatoxin treatment is theoretically effective in the treatment of DO, successful therapeutic
results are not obtained in many patients. The success
rate (including continence rate and rate of improvement)
in recent studies using a single instillation of resiniferatoxin at concentrations of 50 nM to 100 nM was reported
to be about 50% or less [65,85]. The therapeutic effect
of multiple low dose resiniferatoxin was significantly
superior to a placebo, indicating that desensitization of
vanilloid receptors in the bladder can reduce DO and
improve urinary incontinence [76,77].
The success rate with multiple intravesical instillations of resiniferatoxin at a concentration of 10 nM is
PPT
D. Y. Chen, H. C. Kuo
higher than that using a single instillation of resiniferatoxin at a concentration of 50 or 100 nM [65,85], suggesting that a single intravesical instillation of 50 or 100
nM resiniferatoxin might not achieve adequate
desensitization. In previous double-blind, placebo-controlled trials of intravesical resiniferatoxin for spinal
detrusor overactivity, the effect of resiniferatoxin on
increasing bladder capacity was controversial [84,86].
The therapeutic effect of a single instillation of resiniferatoxin might be affected by several factors, such as urine
dilution during the treatment, or reflexic expulsion of
the instilled solution. These factors may result in unknown concentrations actually administered into the
bladder and could result in diverse therapeutic results
[85]. Repeated instillations might lead to greater desensitization of afferent fibers and can provide a satisfactory therapeutic outcome in the majority of patients [77,
87].
TREATMENT OF OVERACTIVE BLADDER BY
BTX-A
BTX-A treatment of NDO due to spinal cord lesion
was reported to provide satisfactory results [55]. Detrusor underactivity developed after detrusor injection of
300 U of BTX-A and lasted for 9 months [55]. Seventythree percent of patients with neurogenic bladder resumed a continent condition after treatment. Achievement of urinary continence and an increase in bladder
capacity seem promising. However, the results for patients with non-neurogenic DO were not as good as NDO
[56].
The lamina propria sensory nerves have been implicated in the responses of the bladder to stretch and
chemical stimulations, which could be associated with
abnormal bladder function such as DO [88,89]. BTX-A
can cause muscle paralysis by blocking ACh release at
the neuromuscular junction [90]. Recently, BTX-A was
used successfully in the treatment of myofascial pain
syndrome, migraine, and other types of headache independent of muscular paralysis [60]. In a model of pain
associated with formalin induced inflammation, rats pretreated with BTX-A displayed significantly decreased
pain behaviors [61]. Reduction of expressions of P2X3
and TRPV1 receptors on suburothelial sensory fibers
have been observed in patients receiving detrusor BTXA injections for DO and have been associated with reduction in the degree of urgency in patients with a successful therapeutic result. An antinociceptive effect
through a direct decrease in the amount of neuropeptides such as substance P and CGRP released from acti-
PPU
vated sensory neurons has been postulated to account
for the clinical effectiveness of BTX-A in pain relief
[61,62]. Nociceptive sensory fibers and stretch sensing
fibers are abundant in the suburothelial space [32,35]. If
BTX-A delivered directly to the suburothelial space
modulates the release of neurotransmitters from sensory
nerve endings, it might effectively inhibit the occurrence
of DO mediated by sensory nerve dysfunction [19].
In previous studies using BTX-A for IDO, most investigators used detrusor injections of 200 U or 300 U.
The therapeutic results varied greatly. Kessler et al
treated 11 patients with IDO with detrusor injections of
300 U BTX-A and the maximal bladder capacity increased from 220 to 340 mL. However, 4 patients needed
clean intermittent catheterization (CIC) due to large
postvoid residuals [91]. Rajkumar et al treated 15 IDO
women with detrusor injections of 300 U BTX-A and
14 had improvements in urgency and frequency. The
therapeutic effects lasted for 5-6 months [92]. Popat et
al used 200 U BTX-A for 31 IDO patients. Although
significant improvement in bladder capacity was noted
after treatment, 20% of the patients needed CIC [93].
Schulte-Baukloh et al used 300 U of BTX-A detrusor
and urethral injections for 7 women with OAB without
DO. The bladder capacity increased by 20% and all patients could void without the need for CIC [94]. In the
author's previous study, detrusor injections of 200 U
BTX-A provided a 73.3% success rate in 30 IDO
patients, with a mean therapeutic duration of 5.3 months
[56]. Further study using suburothelial injections of
BTX-A at a dose of 200 U revealed therapeutic results
(85% success rate) as good as those achieved with 300
U BTX-A in other studies [57]. In another recent study
comparing 200 U, 150 U and 100 U of BTX-A, we found
that 100 U also had excellent therapeutic effects in IDO
(73.3%) when compared with the results of 200 U.
However, there was a higher failure rate in NDO [95].
There is no consensus about the optimal dose of
BTX-A in treatment of refractory OAB or DO. An injection of 300 U of BTX-A is most commonly used for
NDO, whereas 200-300 U have been applied in treating
IDO. The effects of 200 U BTX-A on IDO were similar
with suburothelial injections and detrusor injections
when compared with previous reports. This is possibly
due to the diffusion of the toxin between the detrusor
and the suburothelial space, as shown by a decrease in
sensory fibers in the suburothelial space after detrusor
injection of BTX-A. However, patients receiving
suburothelial injections of 200 U of BTX-A had a higher
rate of adverse events compared to those receiving detrusor injections of the same dose [95].
Recently, the dose of BTX-A for IDO was further
Tzu Chi Med J 2006 18 No. 5
Treatment of LUTS and OAB
reduced to 100 U by many investigators and a satisfactory outcome was still achieved. Werner et al treated 26
women with IDO with a 53% success rate [96]. Schmid
et al treated 100 IDO patients with an 88% success rate
[97]. However, the therapeutic effects of 100 U BTX-A
need further clarification. A dose related increase in adverse events has been found with increasing doses of
BTX-A [95]. In a recent report by the author, urinary
tract infection occurred in 35% of patients, a large
postvoid residual requiring CIC in 30%, and difficult
urination in 75% [57]. This high incidence might prohibit patients receiving a second injection when their
LUTS relapse. A 100 U dose of suburothelial BTX-A
reduced the rates of urinary tract infection to 4.3%, a
large postvoid residual to 30.4%, and difficult urination
to 56.5% [95]. Therefore, adjustment of the dose of BTXA for IDO patients seems mandatory to minimize de
novo adverse events. .
One important factor for a successful therapeutic
outcome with BTX-A is adequate distribution of toxin
into the suburothelial space and detrusor muscles. Desensitization of the mechanoreceptors on suburothelial
sensory fibers can result in a decrease in the bladder
urgency sensation and a reduction of sensory neuropeptide-mediated detrusor overactivity [19]. Injection of
BTX-A into detrusor muscles can cause paralysis of the
affected muscle fibers [56,91-93]. Together, these effects can decrease the bladder sensation and increase
bladder capacity. However, if the BTX-A is not adequately distributed into the bladder wall, or the toxin is
injected outside the bladder wall, the desired effect might
not be achieved. This might explain why some investigators used large doses of BTX-A in detrusor injections
but the therapeutic effects were similar to those with
suburothelial BTX-A injections [57,94]. It is possible
that much of the BTX-A solution is injected too deep
and outside the bladder wall with detrusor injections. In
order to achieve a favorable therapeutic result,
suburothelial injection of BTX-A seems to be a better
route of injection than direct injection into the detrusor
muscle.
Although suburothelial injections of BTX-A have
effects on sensory fibers, detrusor contractility can also
be impaired after treatment [56,57,91-94]. The extent
of detrusor underactivity might be even greater than after detrusor injections of BTX-A at the same dose. For
patients with detrusor overactivity and impaired contractility (DHIC), this adverse event might cause large
postvoid residuals and urinary tract infection. To prevent this undesired adverse event, the dose of BTX-A
and injection sites should be carefully adjusted.
The trigone and bladder base have been found to
Tzu Chi Med J 2006 18 No. 5
have abundant sensory fibers. Injections of BTX-A into
these areas have been shown to have therapeutic effects
on idiopathic urgency frequency syndrome and interstitial cystitis [98]. Although the trigone of the urinary bladder is rich in sensory fibers, the role of trigonal sensory
fibers on bladder urgency sensation and DO has not been
explored yet. The embryology and function of the trigone
are different from bladder body. The trigone is composed of superficial and deep smooth muscles which are
innervated by adrenergic fibers and are believed to relate to the competence of the ureterovesical junctions as
well as the internal sphincter, the so-called 'lissosphincter". The sensation from the trigone might be related
to bladder emptying rather than storage. Hence, treatment aimed at reducing sensation from the trigone might
not improve the urgency sensation occurring during the
bladder filling phase. In addition, paralysis of trigonal
muscles by BTX-A might decrease the tone of muscles
controlling competence of the ureterovesical junction
or bladder neck, resulting in vesicoureteral reflux or bladder neck incompetence. Although vesicoureteral reflux
might be a potential complication after BTX-A in these
areas, there is no evidence of it so far. An advantage of
trigonal injections of BTX-A is that detrusor underactivity does not develop after treatment.
CHRONIC INTERSTITIAL CYSTITIS AND
TREATMENT
Interstitial cystitis (IC) is a debilitating chronic disease of unknown etiology characterized by urgency frequency and suprapubic pain with a full bladder. Current
treatments are usually unsuccessful in completely eradicating bladder pain and increasing bladder capacity [59].
Urothelial dysfunction, overexpression of suburothelial
sensory receptors and central sensitization have all been
speculated as the pathogenesis of sensory urgency and
bladder pain symptoms [99]. Recent investigations suggest that the lamina propria of the bladder plays an important role in transmitting the sensation of bladder fullness and in the response of the bladder to chemical
stimuli and inflammation [23,26,35]. Release of NGF,
CGRP, substance P, and ATP increase in IC [21,100,
101]. Overexpression of TRPV1 and P2X3 receptors on
sensory nerves are also reduced after BTX-A treatment
for OAB as well as IC [19].
In recent decades, treatment of chronic IC has not
substantially progressed. Intravesical resiniferatoxin was
once considered effective but a large scale multiple center trial did not confirm this [102]. Other intravesical
therapies such as hyaluronic acid and BCG, and oral
PPV
D. Y. Chen, H. C. Kuo
medications such as pentosan polysulphate, cyclosporine
A, and amitriptyline have not been demonstrated effective in the long-term [103]. Hydrodistention is still the
most popular treatment for refractory IC. Since BTX-A
has been shown to have effects on both motor and sensory nerve function, it is rational to use BTX-A treatment for this painful bladder syndrome.
Currently, there is no satisfactory treatment for bladder hypersensitivity and IC. Although a leaky urothelium
has been speculated to cause chronic inflammation of
the bladder, intravesical heparin therapy and oral pentosan polysulphate could not eradicate bladder pain and
intractable frequency in most patients with chronic IC
[58,104], suggesting restoration of epithelial function
can only partially repair the pathophysiology but not the
inflammatory or possible central sensitization pain process that characterizes IC.
Although BTX-A is effective in the treatment of
NDO and IDO [55-57,98], there have only been a few
studies using BTX-A in treatment of IC [78,105]. In recent basic research, BTX-A inhibited not only the release of ACh and norepinephrine, but also that of ATP,
substance P and CGRP from the detrusor muscle and
urothelium [16-19]. In clinical experiments, BTX-A reduced DO, impaired bladder sensation, and decreased
visceral pain in chronic inflammatory diseases [38,56,
57,98]. These results suggest that BTX-A treatment can
modulate sensory transmission as well as reduce detrusor contractility. However, the author's previous trial of
100 U BTX-A in the treatment of chronic IC did not
provide satisfactory results, although the measured parameters had significant improvement [105]. It is possible that inadequate distribution of BTX-A to the bladder wall, an inadequate dose of toxin, or a lack of some
promoting factors increases bladder wall dysfunction.
The suburothelial space immediately below the basal
lamina is well supplied with sensory nerves which transmit the sensation of bladder fullness and response to
bladder inflammation [9,35]. These afferent functions
are believed to be mediated through the capsaicin receptor TRPV-1 and ATP-gated ion channel P2X3 on the
sensory neurons of the human urinary bladder [35]. A
local inflammatory process might be induced through
the afferent and efferent nerves in the suburothelial interstitial cellular network which integrate the transmission of signals from the urothelium to the detrusor
muscles in the bladder wall [106]. The release of substance P, CGRP, and NGF from sensory nerves on stimulation were increased during inflammation and reduced
after BTX-A treatment. Intravesical NGF administration can sensitize bladder afferent fibers through changes
in the conduction of afferent ions. Intravesical instilla-
PQM
tion of NGF can induce bladder hyperactivity in rats
while in a rat chemical cystitis model [45], detrusor injection of BTX-A has been shown to have therapeutic
effects in increasing bladder capacity and compliance
[107]. In this regard, inhibition of neuroplasticity of the
sensory fibers in the suburothelial space by intravesical
BTX-A injections might have good therapeutic effects
on pain and sensory urgency in patients with chronic
IC.
BTX-A induced inhibition of rapid afferent firing
has been demonstrated by a reduction of fos-positive
cells in the dorsal horn of formalin-challenged rat models [108]. Increased central c-fos expression has been
demonstrated in animal models of NDO and chronic
bladder inflammation [109]. NGF has been demonstrated
to activate TRPV1 on small afferent nerves, which can
promote release of substance P and induce neurogenic
inflammation. Reduction of NGF production could lead
to inhibition of neurogenic inflammation and further
peripheral desensitization [101]. In treatment of chronic
IC, this effect might have an important role in reducing
bladder pain. If we can inject BTX-A into the detrusor
or suburothelium repeatedly, neurogenic inflammation
in the dorsal root ganglia or central nervous system
(sacral cords in IC) might be eliminated gradually and
the visceral pain can thus be relieved. However, the bladder capacity might not increase if we only inhibit the
sensory pathway or desensitize the central nervous
system.
Previous investigations of BTX-A on IC did not
show uniform results. Smith et al noted a 67% success
rate with a therapeutic duration of 9 months [38].
Giannantoni et al found 85.7% of patients had improvement but the duration was only 3 months [110]. Kuo
reported a significant improvement of measured parameters in 8 patients but only 2 patients declared they were
satisfied with treatment outcome [105]. The causes for
unsuccessful therapeutic results or short therapeutic duration might be due to inadequate desensitization of the
central nervous system Further trials using new treatment modalities such as repeat intravesical injections of
BTX-A, possibly combined treatment with hydrodistention might have a higher success rate and a longer
therapeutic duration in the patients with severe chronic
IC refractory to conventional medical treatment.
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