Treatment of Lower Urinary Tract Symptoms and Overactive Bladder - Focus on Bladder Sensory Innervation
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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 neu-
ropeptide 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 inter-
stitial 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)
IN MEN
Lower urinary tract symptoms (LUTS) consist of a
complex of bladder storage and emptying symptoms. LUTS are highly prevalent, especially among eld-
Previously, treatment of LUTS was focused on bladder erly men and women, with a negative impact on health-
emptying symptoms and bladder outlet obstruction related quality of life. LUTS are associated with great
(BOO). Recent investigations have discovered that the emotional costs for individuals and substantial economic
sensory innervation of the urinary bladder plays an im- costs for society [1,2]. The prevalence and severity of
portant role in storage as well as emptying LUTS. The LUTS increases with age and the progressive increase
treatment strategy for LUTS should be shifted to aim at in the ageing population has increased the social eco-
the sensory innervation rather than the detrusor muscles. nomic 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 PPPD. Y. Chen, H. C. Kuo
LUTS are comprised of storage symptoms (includ- women have symptoms suggestive of OAB [10]. This
ing frequency, urgency, nocturia, and incontinence), figure is far less than that in Europe where 16% of women
voiding symptoms (including hesitancy, intermittency, were reported to have storage symptoms suggestive of
residual urine sensation, straining to void and poor OAB [6]. In addition to OAB symptoms, women also
stream) and postvoid symptoms (incomplete emptying have voiding symptoms such as dysuria, intermittency,
and terminal dribbling). The pathophysiology of LUTS residual sensation and urinary retention suggestive of
could be bladder dysfunction (bladder hypersensitivity, bladder outlet dysfunction or obstruction. In a large scale
detrusor overactivity (DO), detrusor underactivity), BOO videourodynamic study of women with LUTS, BOO was
(bladder neck dysfunction, prostatic obstruction, urethral found in about 9% of women with LUTS refractory to
stricture, poorly relaxed urethral sphincter, urethral medical treatment [11].
sphincter dyssynergia) or a combination of these etiolo- OAB symptoms are well correlated with DO,
gies [4]. Many men have both storage and voiding however, voiding symptoms correlate poorly with BOO.
symptoms. In men voiding symptoms are more common, A study applying the American Urological Association
but storage symptoms are encountered frequently [5]. (AUA) symptom index for LUTS, revealed symptom
The frequent co-morbidity with prostatic diseases in men scores on the storage and voiding subscales did not dif-
adds complexity to the diagnosis and management of fer significantly between men and women from 55-79
male LUTS. years old [12]. In another study from Japan, comparable
Recent investigations of male LUTS noted that blad- storage symptom scores on the International Prostate
der dysfunction plays an important role, in addition to Symptom Score (IPSS) were noted in men and women
BOO. LUTS suggestive of an overactive bladder (OAB) over 40 years old [13]. In a group of men and women
have been estimated to be present in 16% of people in with persistent storage symptoms, 89% of patients whose
Europe and United States [6]. A multinational large scale primary symptoms were frequency and urgency had
study revealed that 90% of men aged 50 to 80 years urodynamic DO [14]. These data suggest that both men
suffer from potentially troublesome LUTS and many and women have storage and voiding symptoms and can
men have both storage and voiding symptoms [3]. Be- be assessed with identical symptom score questionnaires
nign prostatic hyperplasia (BPH) is often associated with such as the AUA or IPSS symptom indexes.
male LUTS, but LUTS cannot be used to make a defi-
nite diagnosis of BPH. LUTS can occur in women,
children, and also in men with either poor detrusor func- THE UROTHELIUM AND OVERACTIVE
tion or BOO. OAB symptoms comprise the same symp- BLADDER
toms as storage LUTS and their prevalence increases
with age. Since most men with OAB do not experience The urinary bladder urothelium had been viewed as
incontinence [7], men with storage LUTS are often mis- a passive barrier, however, recent evidences demon-
diagnosed with clinical BPH. Storage symptoms corre- strated that the urothelium is a responsive structure which
late poorly with BOO, male OAB symptoms may be exhibits both sensor (ability to respond to thermal, me-
caused by bladder dysfunction such as DO or impaired chanical and chemical stimuli) and transducer (ability
detrusor contractility, or occur in combination with BOO to release chemicals) functions. Studies have also re-
[4]. BOO may cause DO, however, many studies have vealed that afferent nerves and urothelial cells in the blad-
reported only 45%-50% of men with LUTS have der exhibit a number of common properties, including
urodynamically confirmed DO and BOO [8,9]. 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
LUTS IN WOMEN be targets for transmitter release from bladder nerves or
that chemicals released by urothelial cells may alter af-
LUTS are more prevalent in women than in men. ferent excitability. The alteration in afferent nerves or
The influence of ageing, menopause and childbirth add urothelial cells in pelvic viscera may contribute to the
complexity to the etiology of female LUTS. OAB symp- sensory abnormalities in the urinary bladder [15].
toms are frequently mixed with stress urinary Recent investigations have shown suburothelial in-
incontinence. The ageing process results in intrinsic ure- nervation expressing the capsaicin receptor TRPV1 [16],
thral sphincteric deficiency which increases the preva- the purinergic receptor P2X3 [17], and the sensory neu-
lence of urinary incontinence and may potentiate DO ropeptides substance P and calcitonin gene-related pep-
and OAB symptoms. In Taiwan, about 10% of men and tide (CGRP) [18] in the pathophysiology of human DO.
PPQ Tzu Chi Med J 2006 18 No. 5Treatment of LUTS and OAB
Patients with neurogenic detrusor overactivity (NDO) cal vanilloid therapy using capsaicin or resiniferatoxin
due to spinal cord lesions were found to have increased acts on the vanilloid receptor TRPV1 and is an effective
TRPV1 and P2X3 immunoreactive suburothelial inner- therapy in patients with detrusor hyperreflexia due to
vation compared to controls [19]. Women with idiopathic spinal cord lesions [34]. TRPV1 receptors are found on
detrusor overactivity (IDO) were found to have increased the afferent nerves in the lamina propria and co-localize
density of suburothelial substance P and CGRP immu- with acetylcholine- containing nerve fibers as well as
noreactive fibers compared to controls [18]. substance P and CGRP in rat bladders [23,26,35].
The urothelial release of neurotransmitters such as Under some pathological conditions in the urinary
acetylcholine (ACh), adenosine triphosphate (ATP) and bladder, such as infection or trauma, the production of
the neuropeptide substance P, and the expression of transmitters such as ATP, substance P, and CGRP can
TRPV1 and P2X3 receptors strongly imply a role for the act on nearby tissues and on afferent nerve terminals in
urothelium in human bladder mechanosensation [20-22]. an autocrine fashion to increase afferent nerve activity
Recent investigations also discovered a suburothelial [36]. The production and release of these neurotrans-
nexus of myofibroblasts or interstitial cells may be the mitters increase during conditions of inflammation and
substrate for a stretch-receptor organ. These cells are pain [37,38]. The suburothelial interstitial cells may be
extensively linked by gap junctions and may respond to affected and sensory transmission occurs earlier, increas-
ATP in a mode similar to the activation of ATP-gated ing the sensation of bladder fullness or mediating detru-
P2Y receptors [23,24]. The urothelial release of ACh sor contraction through a gap junction extending into
and ATP on bladder filling increases with ageing [20] the detrusor muscles [39,40]. Moreover, many C fibers
and in spinal cord NDO [25], implicating an abnormal in the bladder mucosa contain sensory neuropeptides
release of these neurotransmitters in the pathophysio- (such as substance P, neurokinin A, CGRP) which on
logy of DO. In treatment of IDO with intradetrusor in- release, can modulate the micturition reflex and might
jection of botulinum toxin type A (BTX-A) decreased cause detrusor overactivity [25]. A local inflammatory
immunoreactivity of P2X3 expression in suburothelial process might be induced through the afferent and ef-
fibers was noted, which correlated with improvement in ferent nerves in these interstitial cellular networks which
patients' sensation of urgency [19]. integrate signal transmission from the urothelium to
The actual pathophysiology of detrusor overactivity detrusor muscles in the bladder wall [41].
after neurogenic lesions, BOO and ageing has not been In the urinary tract, nerve growth factor (NGF) is
well elucidated. Recently, the urothelium and suburo- produced by bladder smooth muscle and urothelium.
thelial space have received renewed interest because of Recent work indicates that NGF is involved in the on-
their possible roles not only in mediating solute trans- going regulation of neural function, as well as in inflam-
port but also in sensing bladder fullness [26]. An abun- mation and pain. Clinical and experimental data also link
dance of suburothelial sensory nerves and vesicles con- increased levels of NGF in the bladder tissue and urine
taining ACh and ATP in nerve fiber terminals have been to painful inflammatory conditions in the lower urinary
found in the human bladder wall, suggesting the lamina tract, such as interstitial cystitis and chronic prostatitis
propria of the bladder plays an important role in the trans- [42-44]. Bladder inflammation by intravesical irritants
mission of sensation of bladder fullness and in the blad- or in chronic interstitial cystitis leads to acute afferent
der response to stretch [27-29]. These stretch-sensing nerve activity [45] and to long-term plasticity that low-
apparatus may transmit sensory signals as well as medi- ers the threshold for nociceptive and mechanoceptive
ate the detrusor reflex [30]. A change in hydrostatic pres- afferent fibers [46]. Chronic sensitization of afferent fi-
sure on the apical face of the urothelium results in ATP bers might involve both peripheral and central
generation which is postulated to activate P2X3 recep- mechanisms. Intravesical irritants cause increased ex-
tors on sensory nerves [31]. The P2X3 receptors are co- pression of the c-fos protein in the lumbosacral spinal
localized with VR-1 receptors and are believed to be cord [47]. A rise in bladder NGF in the muscle or
involved in afferent pathways that control urinary blad- urothelium initiates signals that are transported along
der volume reflexes [32]. Increased stretch activated ATP bladder afferent nerves to the dorsal root ganglion or
release has been reported from human urothelial cells spinal cord [48]. NGF levels are elevated in the blad-
cultured from the bladders of patients with interstitial ders of men with BOO, patients with OAB and women
cystitis and spinal cord injury. with interstitial cystitis [48,49]. Intravesical BTX-A re-
In the mammalian bladder, unmyelinated sensory duces levels of NGF in the bladder of IDO as well as
afferent C-fibers become predominant and mediate de- NDO [50]. Although the mechanism for the reduced
trusor reflex after spinal cord transection [33]. Intravesi- bladder NGF has not been elucidated, prevention of neu-
Tzu Chi Med J 2006 18 No. 5 PPRD. Y. Chen, H. C. Kuo
ral plasticity by blockade of NGF production has been be applied in patients with OAB.
postulated to cause reduction of urge incontinence and There is not yet a conclusion on the pathophysio-
symptoms of OAB [50]. logy of hypersensitive bladder and OAB. Although
Based on the results from recent investigations, blad- urothelial dysfunction and changes in the urinary potas-
der disorders such as NDO, IDO, OAB due to BOO, sium concentration have been proposed to account for
interstitial cystitis and urothelial dysfunction might have this condition, treatments aimed at these pathophysiolo-
a common pathway in the abnormality of expression of gies have not been able to improve this condition ad-
sensory receptors or release of transmitters in the equately [58,59]. It is possible that the chronic symp-
suburothelial nerves or interstitial cells [41]. In this tomatology in bladder hypersensitivity is due to central
regard, inhibition of receptor expression or transmitter sensitization and persisting abnormality or activation of
release in the sensory nerve terminals in the suburothelial the afferent sensory system [60]. Intradetrusor injection
space might provide good therapeutic effects in the treat- of BTX-A modulates the release of neurotransmitters
ment of sensory urgency, interstitial cystitis and DO. If from sensory nerve endings, and effectively modulates
these hypotheses can be proven, patients with DO, blad- the inflammatory process mediated by nociceptive af-
der hypersensitivity, and interstitial cystitis refractory ferent nerve dysfunction [61,62].
to conventional treatment can be treated in a totally new Previous investigations in intravesical vanilloid
way without adverse effects. The underlying patho- therapy were aimed at treating NDO due to spinal cord
physiology mediating detrusor hyperreflexia and urgency lesions [34,63,64]. Only a few investigations have used
frequency as well as bladder pain in DO, OAB, and in- capsaicin or resiniferatoxin to treat DO or bladder hy-
terstitial cystitis can also be explored. persensitivity from non-spinal cord lesions [65,66]. As
evidenced by positive ice water test results, overexpress-
ion and hyperactivity of the vanilloid receptors in the
TREATMENT OF OAB BY INTRAVESICAL urinary bladder have been identified in patients with DO
RESINIFERATOXIN due to various non-spinal lesions [67]. Therefore, use of
intravesical vanilloid agonists such as capsaicin or
OAB is a symptom syndrome characterized by ur- resiniferatoxin to treat DO refractory to anticholinergic
gency frequency with or without urge incontinence and agents might be effective.
it may affect quality of life [51]. OAB is diagnosed by Intravesical capsaicin therapy exerts an excellent
subjective symptoms, of which the core symptom is effect in patients with incontinence due to multiple scle-
urgency. Both sensory urgency and DO might be in- rosis or spinal cord injuries [68-70]. However, because
volved in the pathophysiology of this symptom of its irritative effect, patients with non-spinal lesions
syndrome. This condition may wax and wane and is might not be able to tolerate capsaicin therapy.
occasionally associated with symptoms of suprapubic Resiniferatoxin, an ultrapotent capsaicin analog, has been
pain with a full bladder. Current treatments are usually shown to have a clinical effect similar to capsaicin but
unsuccessful in completely eradicating the urgency with less neuronal excitatory effect [71]. Thus, resinifera-
sensation. Behavioral therapy and pelvic floor muscle toxin treatment is more suitable than capsaicin for pa-
training have been tried to relieve this bothersome syn- tients who have normal bladder sensation and OAB [72].
drome [52]. Some patients with OAB and hypersensi- Resiniferatoxin treatment has been demonstrated to
tive bladder may respond to antimuscarinic agents [53], have a therapeutic effect in patients with detrusor hy-
but this treatment has some adverse effects such as perreflexia due to spinal cord lesions [73-75]. At a con-
dizziness, dry mouth, blurred vision, and constipation, centration of 100 nM, resiniferatoxin induced full de-
which are intolerable for some elderly patients [54]. sensitization and successfully treated detrusor hyperre-
Treatment with intra-detrusor BTX-A injections dem- flexia in neurologically impaired patients who did not
onstrated satisfactory results in increasing bladder ca- have improvement after capsaicin treatment [75]. In one
pacity and decreasing the urgency sensation in patients study, a 50 nM solution of resiniferatoxin was found to
with NDO or IDO [55,56]. However, increased postvoid delay or suppress involuntary detrusor contractions dur-
residual volumes and urinary retention which sometimes ing filling cystometry in patients with IDO [65]. These
develop in the first post-treatment month may prohibit findings indicate that desensitization of capsaicin sensi-
its wide-spread application in patients with mild to mod- tive primary afferents by intravesical resiniferatoxin can
erate symptoms refractory to antimuscarinic agents [57]. have a therapeutic effect on hyperactive or sensory dis-
Therefore, it is mandatory to search for an effective al- orders of the urinary bladder.
ternative therapy without serious adverse effects that can The clinical effect of intravesical resiniferatoxin at
PPS Tzu Chi Med J 2006 18 No. 5Treatment of LUTS and OAB a concentration of 100 nM was demonstrated in treating the study group and none in placebo group had effective DO due to non-spinal cord lesions in patients refractory relief of symptoms (p
D. Y. Chen, H. C. Kuo
higher than that using a single instillation of resinifera- vated sensory neurons has been postulated to account
toxin at a concentration of 50 or 100 nM [65,85], sug- for the clinical effectiveness of BTX-A in pain relief
gesting that a single intravesical instillation of 50 or 100 [61,62]. Nociceptive sensory fibers and stretch sensing
nM resiniferatoxin might not achieve adequate fibers are abundant in the suburothelial space [32,35]. If
desensitization. In previous double-blind, placebo-con- BTX-A delivered directly to the suburothelial space
trolled trials of intravesical resiniferatoxin for spinal modulates the release of neurotransmitters from sensory
detrusor overactivity, the effect of resiniferatoxin on nerve endings, it might effectively inhibit the occurrence
increasing bladder capacity was controversial [84,86]. of DO mediated by sensory nerve dysfunction [19].
The therapeutic effect of a single instillation of resinifera- In previous studies using BTX-A for IDO, most in-
toxin might be affected by several factors, such as urine vestigators used detrusor injections of 200 U or 300 U.
dilution during the treatment, or reflexic expulsion of The therapeutic results varied greatly. Kessler et al
the instilled solution. These factors may result in un- treated 11 patients with IDO with detrusor injections of
known concentrations actually administered into the 300 U BTX-A and the maximal bladder capacity in-
bladder and could result in diverse therapeutic results creased from 220 to 340 mL. However, 4 patients needed
[85]. Repeated instillations might lead to greater desen- clean intermittent catheterization (CIC) due to large
sitization of afferent fibers and can provide a satisfac- postvoid residuals [91]. Rajkumar et al treated 15 IDO
tory therapeutic outcome in the majority of patients [77, women with detrusor injections of 300 U BTX-A and
87]. 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
TREATMENT OF OVERACTIVE BLADDER BY significant improvement in bladder capacity was noted
BTX-A after treatment, 20% of the patients needed CIC [93].
Schulte-Baukloh et al used 300 U of BTX-A detrusor
BTX-A treatment of NDO due to spinal cord lesion and urethral injections for 7 women with OAB without
was reported to provide satisfactory results [55]. Detru- DO. The bladder capacity increased by 20% and all pa-
sor underactivity developed after detrusor injection of tients could void without the need for CIC [94]. In the
300 U of BTX-A and lasted for 9 months [55]. Seventy- author's previous study, detrusor injections of 200 U
three percent of patients with neurogenic bladder re- BTX-A provided a 73.3% success rate in 30 IDO
sumed a continent condition after treatment. Achieve- patients, with a mean therapeutic duration of 5.3 months
ment of urinary continence and an increase in bladder [56]. Further study using suburothelial injections of
capacity seem promising. However, the results for pa- BTX-A at a dose of 200 U revealed therapeutic results
tients with non-neurogenic DO were not as good as NDO (85% success rate) as good as those achieved with 300
[56]. U BTX-A in other studies [57]. In another recent study
The lamina propria sensory nerves have been im- comparing 200 U, 150 U and 100 U of BTX-A, we found
plicated in the responses of the bladder to stretch and that 100 U also had excellent therapeutic effects in IDO
chemical stimulations, which could be associated with (73.3%) when compared with the results of 200 U.
abnormal bladder function such as DO [88,89]. BTX-A However, there was a higher failure rate in NDO [95].
can cause muscle paralysis by blocking ACh release at There is no consensus about the optimal dose of
the neuromuscular junction [90]. Recently, BTX-A was BTX-A in treatment of refractory OAB or DO. An in-
used successfully in the treatment of myofascial pain jection of 300 U of BTX-A is most commonly used for
syndrome, migraine, and other types of headache inde- NDO, whereas 200-300 U have been applied in treating
pendent of muscular paralysis [60]. In a model of pain IDO. The effects of 200 U BTX-A on IDO were similar
associated with formalin induced inflammation, rats pre- with suburothelial injections and detrusor injections
treated with BTX-A displayed significantly decreased when compared with previous reports. This is possibly
pain behaviors [61]. Reduction of expressions of P2X3 due to the diffusion of the toxin between the detrusor
and TRPV1 receptors on suburothelial sensory fibers and the suburothelial space, as shown by a decrease in
have been observed in patients receiving detrusor BTX- sensory fibers in the suburothelial space after detrusor
A injections for DO and have been associated with re- injection of BTX-A. However, patients receiving
duction in the degree of urgency in patients with a suc- suburothelial injections of 200 U of BTX-A had a higher
cessful therapeutic result. An antinociceptive effect rate of adverse events compared to those receiving de-
through a direct decrease in the amount of neuropep- trusor injections of the same dose [95].
tides such as substance P and CGRP released from acti- Recently, the dose of BTX-A for IDO was further
PPU Tzu Chi Med J 2006 18 No. 5Treatment of LUTS and OAB
reduced to 100 U by many investigators and a satisfac- have abundant sensory fibers. Injections of BTX-A into
tory outcome was still achieved. Werner et al treated 26 these areas have been shown to have therapeutic effects
women with IDO with a 53% success rate [96]. Schmid on idiopathic urgency frequency syndrome and intersti-
et al treated 100 IDO patients with an 88% success rate tial cystitis [98]. Although the trigone of the urinary blad-
[97]. However, the therapeutic effects of 100 U BTX-A der is rich in sensory fibers, the role of trigonal sensory
need further clarification. A dose related increase in ad- fibers on bladder urgency sensation and DO has not been
verse events has been found with increasing doses of explored yet. The embryology and function of the trigone
BTX-A [95]. In a recent report by the author, urinary are different from bladder body. The trigone is com-
tract infection occurred in 35% of patients, a large posed of superficial and deep smooth muscles which are
postvoid residual requiring CIC in 30%, and difficult innervated by adrenergic fibers and are believed to re-
urination in 75% [57]. This high incidence might pro- late to the competence of the ureterovesical junctions as
hibit patients receiving a second injection when their well as the internal sphincter, the so-called 'lissosphi-
LUTS relapse. A 100 U dose of suburothelial BTX-A ncter". The sensation from the trigone might be related
reduced the rates of urinary tract infection to 4.3%, a to bladder emptying rather than storage. Hence, treat-
large postvoid residual to 30.4%, and difficult urination ment aimed at reducing sensation from the trigone might
to 56.5% [95]. Therefore, adjustment of the dose of BTX- not improve the urgency sensation occurring during the
A for IDO patients seems mandatory to minimize de bladder filling phase. In addition, paralysis of trigonal
novo adverse events. . muscles by BTX-A might decrease the tone of muscles
One important factor for a successful therapeutic controlling competence of the ureterovesical junction
outcome with BTX-A is adequate distribution of toxin or bladder neck, resulting in vesicoureteral reflux or blad-
into the suburothelial space and detrusor muscles. De- der neck incompetence. Although vesicoureteral reflux
sensitization of the mechanoreceptors on suburothelial might be a potential complication after BTX-A in these
sensory fibers can result in a decrease in the bladder areas, there is no evidence of it so far. An advantage of
urgency sensation and a reduction of sensory neuropep- trigonal injections of BTX-A is that detrusor underac-
tide-mediated detrusor overactivity [19]. Injection of tivity does not develop after treatment.
BTX-A into detrusor muscles can cause paralysis of the
affected muscle fibers [56,91-93]. Together, these ef-
fects can decrease the bladder sensation and increase CHRONIC INTERSTITIAL CYSTITIS AND
bladder capacity. However, if the BTX-A is not ad- TREATMENT
equately distributed into the bladder wall, or the toxin is
injected outside the bladder wall, the desired effect might Interstitial cystitis (IC) is a debilitating chronic dis-
not be achieved. This might explain why some investi- ease of unknown etiology characterized by urgency fre-
gators used large doses of BTX-A in detrusor injections quency and suprapubic pain with a full bladder. Current
but the therapeutic effects were similar to those with treatments are usually unsuccessful in completely eradi-
suburothelial BTX-A injections [57,94]. It is possible cating bladder pain and increasing bladder capacity [59].
that much of the BTX-A solution is injected too deep Urothelial dysfunction, overexpression of suburothelial
and outside the bladder wall with detrusor injections. In sensory receptors and central sensitization have all been
order to achieve a favorable therapeutic result, speculated as the pathogenesis of sensory urgency and
suburothelial injection of BTX-A seems to be a better bladder pain symptoms [99]. Recent investigations sug-
route of injection than direct injection into the detrusor gest that the lamina propria of the bladder plays an im-
muscle. portant role in transmitting the sensation of bladder full-
Although suburothelial injections of BTX-A have ness and in the response of the bladder to chemical
effects on sensory fibers, detrusor contractility can also stimuli and inflammation [23,26,35]. Release of NGF,
be impaired after treatment [56,57,91-94]. The extent CGRP, substance P, and ATP increase in IC [21,100,
of detrusor underactivity might be even greater than af- 101]. Overexpression of TRPV1 and P2X3 receptors on
ter detrusor injections of BTX-A at the same dose. For sensory nerves are also reduced after BTX-A treatment
patients with detrusor overactivity and impaired con- for OAB as well as IC [19].
tractility (DHIC), this adverse event might cause large In recent decades, treatment of chronic IC has not
postvoid residuals and urinary tract infection. To pre- substantially progressed. Intravesical resiniferatoxin was
vent this undesired adverse event, the dose of BTX-A once considered effective but a large scale multiple cen-
and injection sites should be carefully adjusted. ter trial did not confirm this [102]. Other intravesical
The trigone and bladder base have been found to therapies such as hyaluronic acid and BCG, and oral
Tzu Chi Med J 2006 18 No. 5 PPVD. Y. Chen, H. C. Kuo
medications such as pentosan polysulphate, cyclosporine tion of NGF can induce bladder hyperactivity in rats
A, and amitriptyline have not been demonstrated effec- while in a rat chemical cystitis model [45], detrusor in-
tive in the long-term [103]. Hydrodistention is still the jection of BTX-A has been shown to have therapeutic
most popular treatment for refractory IC. Since BTX-A effects in increasing bladder capacity and compliance
has been shown to have effects on both motor and sen- [107]. In this regard, inhibition of neuroplasticity of the
sory nerve function, it is rational to use BTX-A treat- sensory fibers in the suburothelial space by intravesical
ment for this painful bladder syndrome. BTX-A injections might have good therapeutic effects
Currently, there is no satisfactory treatment for blad- on pain and sensory urgency in patients with chronic
der hypersensitivity and IC. Although a leaky urothelium IC.
has been speculated to cause chronic inflammation of BTX-A induced inhibition of rapid afferent firing
the bladder, intravesical heparin therapy and oral pen- has been demonstrated by a reduction of fos-positive
tosan polysulphate could not eradicate bladder pain and cells in the dorsal horn of formalin-challenged rat mod-
intractable frequency in most patients with chronic IC els [108]. Increased central c-fos expression has been
[58,104], suggesting restoration of epithelial function demonstrated in animal models of NDO and chronic
can only partially repair the pathophysiology but not the bladder inflammation [109]. NGF has been demonstrated
inflammatory or possible central sensitization pain pro- to activate TRPV1 on small afferent nerves, which can
cess that characterizes IC. promote release of substance P and induce neurogenic
Although BTX-A is effective in the treatment of inflammation. Reduction of NGF production could lead
NDO and IDO [55-57,98], there have only been a few to inhibition of neurogenic inflammation and further
studies using BTX-A in treatment of IC [78,105]. In re- peripheral desensitization [101]. In treatment of chronic
cent basic research, BTX-A inhibited not only the re- IC, this effect might have an important role in reducing
lease of ACh and norepinephrine, but also that of ATP, bladder pain. If we can inject BTX-A into the detrusor
substance P and CGRP from the detrusor muscle and or suburothelium repeatedly, neurogenic inflammation
urothelium [16-19]. In clinical experiments, BTX-A re- in the dorsal root ganglia or central nervous system
duced DO, impaired bladder sensation, and decreased (sacral cords in IC) might be eliminated gradually and
visceral pain in chronic inflammatory diseases [38,56, the visceral pain can thus be relieved. However, the blad-
57,98]. These results suggest that BTX-A treatment can der capacity might not increase if we only inhibit the
modulate sensory transmission as well as reduce detru- sensory pathway or desensitize the central nervous
sor contractility. However, the author's previous trial of system.
100 U BTX-A in the treatment of chronic IC did not Previous investigations of BTX-A on IC did not
provide satisfactory results, although the measured pa- show uniform results. Smith et al noted a 67% success
rameters had significant improvement [105]. It is pos- rate with a therapeutic duration of 9 months [38].
sible that inadequate distribution of BTX-A to the blad- Giannantoni et al found 85.7% of patients had improve-
der wall, an inadequate dose of toxin, or a lack of some ment but the duration was only 3 months [110]. Kuo
promoting factors increases bladder wall dysfunction. reported a significant improvement of measured param-
The suburothelial space immediately below the basal eters in 8 patients but only 2 patients declared they were
lamina is well supplied with sensory nerves which trans- satisfied with treatment outcome [105]. The causes for
mit the sensation of bladder fullness and response to unsuccessful therapeutic results or short therapeutic du-
bladder inflammation [9,35]. These afferent functions ration might be due to inadequate desensitization of the
are believed to be mediated through the capsaicin re- central nervous system Further trials using new treat-
ceptor TRPV-1 and ATP-gated ion channel P2X3 on the ment modalities such as repeat intravesical injections of
sensory neurons of the human urinary bladder [35]. A BTX-A, possibly combined treatment with hydrodis-
local inflammatory process might be induced through tention might have a higher success rate and a longer
the afferent and efferent nerves in the suburothelial in- therapeutic duration in the patients with severe chronic
terstitial cellular network which integrate the transmis- IC refractory to conventional medical treatment.
sion of signals from the urothelium to the detrusor
muscles in the bladder wall [106]. The release of sub-
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