CHALLENGE OF OVERACTIVE BLADDER THERAPY: ALTERNATIVE TO ANTIMUSCARINIC
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of Urology (ML), Casa di Cura Santa Chiara Firenze, and Department of
Neurourology (MS), Spinal Unit Ospedale Ca’ Grande, Niguarda, Milan,
the management of overactive bladder (OAB), a medical condition characterized
by urgency, with or without urge urinary incontinence, frequency and nocturia,
in absence of genitourinary pathologies or metabolic factors that could
explain these symptoms, is complex, and a wide range of conservative treatments
has been offered, including bladder training, biofeedback, behavioral
changes, oral or intravesical anticholinergic agents, S3 sacral neuromodulation
and peripheral electrical stimulation. Clinical efficacy of these treatments
remains an open issue and several experimental and clinical studies were
carried out in the last years improving the results of medical treatment.
Here we review the pathophysiology of micturition
reflex, the current therapies for OAB and the rationale for alternative
treatments. Furthermore we critically address the potential use of medications
targeting the central nervous system (CNS) and the primary sensory nerves
of the bladder wall, we review the use of agonists of nociceptin/orphanin
protein (NOP) receptor and finally we report the results obtained by intradetrusor
injection of botulinum toxin.
words: overactive bladder; voiding dysfunction; pharmacotherapy;
receptor, orphanin fq; botulinum toxins
Int Braz J Urol. 2006; 32: 620-30
bladder (OAB) is a medical condition characterized by urgency, with or
without urge urinary incontinence, frequency and nocturia, in absence
of genitourinary pathologies or metabolic factors that could explain these
symptoms (1). This definition represents an important clinical message
because in the era of High-Tech medicine, people look for medical help
in the same way as in the past as a result of symptoms. The key symptom,
which characterizes OAB, is “urgency”: the sudden and compelling
desire to pass urine, which is difficult to defer.
OAB affects one sixth of European population
aged 40 years or over (2) and similar data have been reported also for
United State of America where around one sixth of adults aged 18 years
and over have symptoms of OAB; the estimated prevalence is 33 million
US residents aged over 18 years (3). Recently Erwin reported a cross-sectional
population-based survey of people > 18 years showing that the total
prevalence in 4 European countries is 12.2% and confirmed that OAB is
a common condition in men and women across all adult age group (4). One
third of people with overactive bladder have urge urinary incontinence
and large population studies have reported that the prevalence of symptoms
of OAB increases with age (5).
The aim of this paper is to address critically
the therapy of OAB providing an up-to-dated insight on alternative strategies
PATHOPHYSIOLOGY OF MICTURITION REFLEX
lower urinary tract serves two main functions: the storage of urine without
leakage (storage phase) and the periodic release of urine (voiding phase).
During the storage phase the detrusor muscle is relaxed and the outlet
region is contracted to maintain continence. During the voiding phase
the detrusor muscle contracts and the outlet region relaxes facilitating
bladder emptying. These two functions are dependent on central, peripheral
autonomic and somatic neuronal pathways and local peripheral factors.
During the storage phase the afferent impulses reach the central nervous
system (CNS) from the lower urinary tract and afferent activity sends
information to the periaqueductal grey of pons. In the pontine tegmentum
there are two regions: a medially located one (M-region), which corresponds
to Barrington’s nucleus or pontine micturition center which is responsible
of coordination of micturition reflex (6), and a laterally located one
(L-region), which is involved in the storage phase suppressing the bladder
contraction and improving external sphincter muscle activity during this
phase (7). The emerging development of functional imaging such as single
photon emission tomography (SPET), positron emission tomography (PET)
and functional MRI showed several sovraspinal-sovrapontine (cortical)
areas involved in the micturition reflex, but so far their specific role
remains obscure (8-10).
Three different sets of peripheral neuronal
systems are involved in the micturition reflex: the parasympathetic system
the sympathetic system and the somatic system. The parasympathetic system
originates in the sacral level of the spinal cord (S2-S4) and provides
an excitatory input to the bladder by the postganglionic nerve terminal
release of Acetylcholine (Ach), which excites muscarinic receptors (M2,
M3) in the detrusor smooth muscle leading to the bladder contraction.
The sympathetic system originates in the thoracolumbar cord (Th11-L2)
and provides an inhibitory input to the bladder by the postganglionic
nerve terminal release of norepinephrine (NA) which excites b3 receptors
in the body of the detrusor leading to the bladder relaxation. The sympathetic
system also provides an excitatory input to the urethra smooth muscle
by the postganglionic nerve terminal release of norepinephrine (NA) which
excites a1 receptors in the urethra leading to the urethral closure. The
somatic system provides an excitatory input to the striated urethral muscle;
in this case the motoneurons are located along the lateral border of the
ventral horn of the sacral spinal cord, which is known as the Onuf’s
nucleus. They release Ach, which acts on nicotinic receptors to induce
Immunohistochemical and morphological studies,
which have been conducted on the bladder wall, showed that there are a
lot of neuronal terminal endings that do not correspond to cholinergic
and adrenergic innervations (11). These nerves, which are non adrenergic
- non cholinergic (NANC), are peptide containing fibers and they are selectively
sensitive to capsaicin, the pungent ingredient of red peppers, heat and
H+. They are primary afferents and may play an important role in the regulation
of lower urinary tract functions (12). These nerves consist of small myelinated
Ad and un-myelinated C fibers, which are, however, “silent”
under normal conditions.
Data from several laboratories have recently
shown the importance of peripheral local factors in the regulation of
micturition reflex. The bladder urothelium can respond to chemical and
mechanical stimuli releasing different mediators, which target the receptors
of adjacent sensory nerves (13). Birder introduced the concept of “neuron-like
properties” of urothelium. Urothelium responds to stretch, during
the filling phase of micturition reflex, by increasing the size of apical
umbrella cells and by releasing mediators, which activate sensory fibers
(14). Finally several investigators suggest a regulatory role for interstitial
cells, which are part of a “vesical module” consisting of
nerves, smooth muscle cells and interstitial cells. It is thought that
this module may receive diverse inputs and may be able to modulate local
reflex or activity (15).
OAB may result from increased bladder afferent
activity, decreased capacity to handle afferent information or decreased
suprapontine inhibition in the CNS, and increased peripheral sensibility
to release mediating transmitters. This last situation, known as “bladder
oversensitivity”, could originate from the release of neurotransmitters
by urothelium or sensitization of sensory nerves by paracrine pathways.
The CNS as well as the periphery may represent the target for a new class
of medications against OAB.
FOR OVERACTIVE BLADDER
which antagonist Ach for the muscarinic receptors, are first line pharmacological
treatment for overactive bladder. The indication for the treatment of
OAB derives from a high level of evidence (Level-1) and high grade of
recommendation (Grade-1) (16). Anticholinergics produce significant symptom
improvements in OAB syndromes when they are compared to a placebo and
the number of anticholinergic drugs available on the market is increasing.
However, the debate about the pathophysiological rationale and the clinical
use of antimuscarinic agents remains an unsolved issue.
Herbison reported a systematic review of
anticholinergic drug treatment compared to a placebo therapy in the treatment
of overactive bladder as a result from randomized controlled trials (17).
He found that those patients receiving active treatment were more likely
to be subjectively improved and they had about one leakage episode less
in 48 hours than those taking placebo. Urodynamic assessment showed larger
increase in maximum cystometric capacity in those receiving active treatment
and the volume at first contraction increased more in the drug group than
in the placebo group. Dry mouth was the most frequently reported side
effect. Herbison concluded that although statistically significant, the
differences between anticholinergic drugs and placebo were small, apart
from the increased rate of dry mouth in patients receiving active treatment.
For many of the outcomes studied, the observed difference between anticholinergics
and placebo may be of questionable clinical significance.
After the publication of this paper many
urologists felt that Herbison had inappropriately written off this class
of drugs and that the author had a preconceived notion about anticholinergics.
Chapple et al. carried out a systematic review and a meta-analysis on
the effects of antimuscarinic in the OAB therapy (18). His review was
planned to assess the safety, tolerability and efficacy of antimuscarinic
in the OAB therapy, considering the effects on quality of life (QoL),
differences between different antimuscarinics and, finally, addressing
criticism of Herbison’s review. Chapple’s review has many
differences regarding Herbison’s study. He did a systematic analysis
of QoL data, a differentiation between individual antimuscarinics, including
active controlled trials and following a “splitting” approach
and not a “cumulative” approach. Chapple et al. reported that
antimuscarinic formulations, apart from Oxybutynin IR (immediate release)
were found well tolerated and no drug was associated with a significant
risk of death. Also, in this review dry mouth was the most commonly reported
adverse effect, even if other adverse reactions were included (blurred
vision, constipation, dyspepsia, nausea, vomiting, urinary retention).
Antimuscarinics were able to reduce frequency, urgency episodes by over
one episode per day, incontinence by half an episode or more per day and
the volume voided per micturition was increased. Finally patients receiving
antimuscarinics have greater improvements in QoL than patients on placebo
arm. Chapple et al. (18) concluded that there is a quantifiable objective
and clinical benefit conferred by antimuscarinics in the therapy of OAB.
However, most of the studies, which were
considered in the review, had limitations of evidences such as choice
of outcome measure, trial length, restricted population, the high placebo
effect and economic issues. For all these reasons, today, many of us are
disputing formally and systematically in order to trigger an appropriate
response to the question on the rational of use of anticholinergics and
for finding alternative therapies.
FOR ALTERNATIVE THERAPIES TO ANTICHOLINERGICS
the past, many factors discouraged the extensive research on new drugs
in the treatment of OAB or LUTS. The main limitations were due to the
complex neuropharmacological arrangement of voiding reflex and sexual
function, the simple “easy to accept” idea of antagonistic,
parasympathetic cholinergic and sympathetic adrenergic control of the
LUT and the complex interrelationship between the voluntary somatic control
of visceral reflex and the involuntary components.
In the last 2 decades the neuropharmacology
gained advantages from basic science research and the experimental results
were translated in the clinical practice. The main advantages were due
to the discovery of non-adrenergic - non-cholinergic innervation (NANC)
of the LUT (19), the recognition of a multiplicity of neurotransmitters
(monoamines, purines, amino acid, peptides and nitric oxide) (11), the
concept of co-transmission (nerves release more than one transmitter)
and the recognition of the basilar importance of a sub set of sensory
nerves which are sensible to capsaicin, the pungent ingredient of red
chilli, in the control of micturition reflex (20). Finally, the discovery
of a new variety of different receptors, involved in the regulation of
sensory nerves’ conduction and changes occurring during not only
development and ageing but also after trauma or chronic inflammation (neuroplasticity),
were basilar for the development of alternative therapies (21-23).
Today CNS, sensory nerves and bladder smooth
muscle cells represents the main targets of alternative strategy for OAB.
CNS transmitters/receptors systems, including adrenoceptors, γ-aminobutyric
acid (GABA), opioid, serotonin, noradrenaline, dopamine, and glutamatergic
receptors are known to be involved in micturition control (24).
Several and different adrenoceptors have
been found in the brain and spinal cord. High levels of α1A mRNA
have been showed in many hypothalamic nuclei, α1A mRNA
and α1B mRNA in amygdala and raphe nuclei and α1D
mRNA in the cortex, hippocampus and amygdala. Different studies showed
that i.t. or i.c.v. α1 antagonists reduced the detrusor
overactivity in the spontaneously hypertensive rat, i.t. or i.c.v. tamsulosine
inhibits the micturition reflex by the activation of spinal receptors
and α2 agonists produce the activation of micturition
reflex by the activation of supraspinal and spinal receptors (25). α1A-,
α1B-, and α1D-AR mRNA can be demonstrated
in the parasympathetic nucleus in the sacral spinal cord (26) and α1d-AR
KO mice vs. wild type controls showed lower voiding frequency, larger
bladder capacity and larger voided volumes (27). Naftopidil and tamsulosin
both block α-ARs in prostatic smooth muscle, and both agents (especially
naftopidil) may also act on the lumbosacral cord (28). It is interesting
report that tamsulosin and aftopidil in a 8-week crossover-study on 96
BPH patients decreased the I-PSS for storage symptoms (29). This study
suggests that naftopidil is as effective and safe as tamsulosin and both
drugs were effective in improving storage and voiding symptoms. However,
there was no difference in clinical efficacy or adverse effects between
the α1 AR antagonists with different affinity to α1
subtypes, α1A and α1D (30).
There has been little interest in developing
drugs active on opioid mechanisms for the treatment of bladder disorders,
despite the profound inhibitory effects that morphine and analogs have
on the micturition reflex. However, tramadol, which is both a µ-receptor
agonist and an inhibitor of noradrenaline and serotonin uptake, has been
reported to have promising effects on micturition in animal models (31).
Tramadol produced the inhibition of detrusor overactivity induced by cerebral
infarction in rats and the inhibition of detrusor overactivity induced
by apomorphine in rats (32).
Serotonin and its receptors may play an
important role in the central regulation of micturition reflex. Exposure
to selective serotonin reuptake inhibitors (SSRIs) is associated with
an increased risk (15/1000 patients) for developing urinary incontinence
especially between the elderly and users of sertraline are at the highest
risk (33). Clomipramine treated female rat pups void more frequently than
controls, have a lower bladder capacity and show detrusor overactivity.
Fluoxetine treatment reverses these effects. Up to date, no convincing
documentation exists whether or not SSRIs are effective in the treatment
of OAB, and despite positive acute effects in preclinical models, there
are no proof of concept studies showing that subtype selective 5-HT receptor
antagonists (5-HT1A, 5-HT7) are effective in the OAB treatment.
In the normal rat, stimulation of GABA receptors,
mainly in the central nervous system, inhibits micturition. Antagonism
of GABAB receptors stimulates micturition, suggesting that
the receptors are under tonic GABAergic influence. Intrathecally baclofen
attenuates oxyhemoglobin induced detrusor overactivity, suggesting that
the inhibitory actions of GABAB receptor agonists in the spinal
cord may be useful for controlling micturition disorders caused by C-fiber
activation in the urothelium and/or suburothelium (34). Recently experimental
studies have demonstrated the inhibitory effect of exogenous gamma-aminobutyric
acid (GABA) on micturition. Tigabine inhibits the micturition reflex in
rat and its site of action, which may be central (35).
Finally, Kim reported the effects of gabapentin
in 14 out of 31 patients with refractory OAB. He found an improvement
of clinical parameters with fewer side effects, gabapentin was generally
well tolerated, and it can be considered in selected patients an alternative
treatment to antimuscarinics.
In conclusion, several promising new principles
have been recently investigated, but only few drugs have passed the stage
of “proof” of concept.
the idea of afferent blockade by targeting afferent nerves that control
the micturition reflex has gained the trust of urologists as a potential
alternative to current drug therapies. The emerging concept is that it
would be more desirable to prevent the micturition reflex that initiates
overactive bladder, instead of blocking the contraction of detrusor smooth
muscle. The concept of a therapeutic approach through the modulation of
the afferent arm of the micturition reflex emerged when investigators
studied the effect of capsaicin on sensory nerves. Capsaicin targets the
transient receptor potential vanilloid-1 (TRPV1), which is expressed on
small-to-medium size afferent neurons, which are most of C-type but also
in a fraction of A-δ type. The acute exposure to capsaicin depolarizes
and excites sensory fibers expressing TRPV1 receptors. This excitation
is followed by a refractory period. It means that the repeated, long-term,
high dose exposure to capsaicin desensitizes, defunctionalizes and ultimately
damages peripheral terminals, which become unresponsive. In other words,
the mechanism of action by which capsaicin works is a long lasting reversible
suppression of sensory nerve activity and it is dependent on dose, time
of exposure and interval between consecutive instillations.
The proof of concept that an inhibitory
modulation of urinary bladder afferent nerves could achieve a therapeutic
benefit in the treatment of bladder overactivity, was obtained through
the intravesical instillation of repeated low concentration doses or single
high concentration doses of capsaicin (20). The first experiences were
performed in patients with neurogenic detrusor overactivity. De Ridder
reported that repeated instillations of intravesical capsaicin was effective
in approximately 80% of the patients with bladder overactivity due to
spinal cord disease and the beneficial effect lasted 3 to 5 years (36).
At the end of the 1990s Lazzeri questioned the efficacy and the safety
of capsaicin for the management of detrusor hyperreflexia (37) and Petersen
demonstrated, in a placebo controlled crossover study, that intravesical
treatment with capsaicin did not show beneficial effects on detrusor hyperreflexia
and produced significant reactive changes in the bladder mucosa (38).
Lazzeri reported that 12.96% of patients had a significant episode of
autonomic dysreflexia during the infusion, 35.18% presented rhythmic detrusor
contractions causing the leakage of urine and 96% of the patients with
incomplete spinal lesion and bladder sensation reported a warm/burning/painful
sensation (39). de Seze, by Bordeaux group, found that the capsaicin side
effects were due to alcohol (the vehicle), which were used, sometimes,
at the concentration of 30%. When capsaicin was diluted in glucidic acid,
intravesical instillation was equally effective with fewer adverse events
(40). Owing to the warm/burning sensation/discomfort that capsaicin produced
in subjects with normal sensation and increasing the regulation of non
licensed agents, the source of capsaicin mostly having been chemical rather
than pharmacological suppliers, was replaced by the pharmaceutically prepared
resiniferatoxin (RTX). RTX, obtained from a cactus species of the genus
Euphorbia, Euphorbia resinifera, is an ultra potent capsaicin analogue
to a thousand fold the selective C-fiber neurotoxicity of capsaicin for
comparable pungency and with fewer side effects. Against a strong scientific
background of its demonstrated mode of action in animal models, the use
of this agent therefore held out the promise of an effective “de-afferenting”
instillation with little discomfort. However , the reality to date has
unfortunately been otherwise. Following early positive reports of its
effectiveness in both neurogenic (41,42) and idiopathic detrusor overactivity
(43) large scale placebo controlled multicentric clinical trials in Europe
and the US were initiated to examine the efficacy of the agent in patients
with neurogenic bladder. During the course of these studies it became
apparent, to those involved in the trials, that many patients were not
responding at all, which lead to a review of the study procedures and
the recognition of the possible loss of active drug availability due to
the adsorptive properties of RTX to plastic. Immunohistochemical evidence
showed that responders had a demonstrable reduction of nerve density of
suburothelial innervations, with a parallel reduction in the expression
of TRPV1 and P2X receptors (44,45) of these nerves.
Other centers continued to examine the efficacy
of RTX in detrusor overactivity (46,47) and because of the known effect
of RTX on afferent innervations, a study looked at its efficacy in conditions
of bladder pain or interstitial cystitis (48). Encouraged by positive
finings, a pharmaceutical company recently funded a large scale placebo
controlled study using RTX to treat interstitial cystitis. Unfortunately
the reported benefits were no greater in the active treatment than the
placebo group and it therefore seems unlikely that a pharmaceutical preparation
of RTX will continue to be made available unless there is some further
development in this field.
Recently experimental and clinical evidence
has showed that the inhibitory system nociceptin/orphanin (NO) FQ - nociceptin/orphanin
protein (NOP) receptor, may play an important role in the modulation of
micturition reflex. Nociceptin inhibits the activity of TRPV1-expressing
neurons at the peripheral level by the activation of a specific G-protein
coupled receptor named nociceptin orphan peptide (NOP) receptor (49).
In a pilot, uncontrolled study, the intravesical infusion of N/OFQ increased
the bladder capacity in a selected group of patients suffering from neurogenic
detrusor overactivity, but not in normal subjects (50). These findings
were replicated in a placebo-controlled randomized study suggesting that
NOP receptor agonists modulate the micturition reflex in humans and they
could represent a suitable alternative to the treatment of OAB to oral
toxin (BTX) is a complex protein, produced by the anaerobic bacterium
Clostridium botulinum. Previously known only as a cause of a serious and
often fatal paralysis acquired through ingestion of contaminated food,
the neuromuscular blocking effect of the toxin has been thought that might
alleviate muscle spasm due to excessive neural activity of central origin.
Local injections of BTX have been showed effective in the treatment of
strabismus, essential blepharospasm, and hemifacial spasm and further
studies indicate that BTX injections also can provide useful symptomatic
relief in a variety of other conditions characterized by involuntary spasms
of certain muscle groups, notably in focal or segmental dystonia including
spasmodic torticollis, oromandibular dystonia (orofacial dyskinesia, Meige
syndrome), and spasmodic dysphonia. Recently the unlicensed use of toxin
in the treatment of lower urinary tract (LUT) conditions has been described.
(52). LUT disorders are characterized by detrusor sphincter dyssynergia
(53,54), detrusor overactivity neurogenic detrusor overactivity (NDO)
(55) and also idiopathic detrusor overactivity (IDO).
Botulinum toxin is thought to work by cleaving
a synaptosome-associated protein, SNAP-25, thereby blocking the presynaptic
release of acetylcholine at the neuromuscular junction. This protein is
part of SNARE complex, which is vital for vesicular exocytosis and relies
of Ach. It is important to remind that, after exposure to botulinum toxin,
neuronal death does not occur, but the phenomenon of re-sprouting of axons,
leading to new synaptic contacts, also occurs and these presumably account
for the return to muscular function, which is observed after a number
of months (56). The re-sprouting of axons might also play a role in hyperactivity
of muscular function or reduction of compliance in case of the bladder
In the last year several investigators suggested
that BTX might affect urothelium/suburothelium sensory innervations. BTX-A
has been found to reduce pathologically elevated levels of neurotransmitters
including ATP, to decrease the number of suburothelial afferent neurons
expressing purinergic receptors and to reduce urgency (57,58). The exact
mechanism of action on the afferent pathway remains unknown.
Following the remarkable efficacy seen in
studies with NDO, a number of researchers have investigated BTX use in
patients suffering from antimuscarinic refractory IDO. Chancellor was
the first to investigate the effect of BOT in a group of patients with
overactive bladder refractory to other conservative treatments (59). Rapp
investigated the effects of injection of botulinum toxin in thirty-five
patients (29 women and 6 men) with frequency, urgency, and/or urge incontinence
(60). The patients received 300 UI of BTX-A injected transurethrally at
30 sites within the bladder. Overall, 21 (60%) of 35 patients reported
slight to complete improvement of voiding symptoms after 3 weeks. Among
the initial responders followed up for 6 months an improvement of quality
of life was reported in most patients with fewer side effects. Due to
the increased understanding of the role of the urothelium in OAB, Kuo
assessed sub-urothelial injections of BTX (61). It was found that although
this method of administration was more effective than detrusor injections,
there was impaired bladder sensation and voiding efficiency. Voiding difficulty
was reported by 75% of patients, and 30% required catheterization. This
suggests that blockade of detrusor contractility through sub-urothelial
sensory fibers was much more pronounced than at neuromuscular junctions
or that only a small amount of diffusion of BTX from the detrusor to the
sub-urothelium occurs following detrusor injection. More recently Schulte-Baukloh
performed BTX injections in patients with refractory OAB symptoms but
with no evidence of DO on prior urodynamics (62). Significant improvements
were seen in symptoms scores, bladder diary and urodynamic parameters.
In this group of patients no increased PVR or need for CISC was noted
even with a dose of 300 UI of BTX. In order to avoid acute urinary retention
or PVR, all patients had 50-75 UI of the BTX concurrently injected into
the external sphincter without increasing stress incontinence rate.
Several studies supported the BTX as promising
therapy in urological disease conditions as previously described, however
additional investigations, including controlled clinical trials, are needed.
Further studies of the mechanism of action of botulinum toxin and its
pharmacotherapeutics are also needed and international standardization
of measures of biological activity of botulinum toxin is requested. We
strongly suggest that for most of urological indications, botulinum toxin
should be used by committed interdisciplinary teams of physicians and
related health care professionals with appropriate instrumentation to
assess the clinical beneficial as well as objective and sub clinical side
effects. The long-term effects of chronic treatment with botulinum toxin
remain unknown. Prolonged follow-up is necessary in patients on maintenance
therapy and an international independent database should be established.
new therapies are supposed to be better than the treatment they replace
and not to induce any side effects. Studies of an alternative treatment
to antimuscarinics for overactive bladder (OAB) are more likely to cite
preliminary studies reporting positive results than equally valid studies,
which use the same compounds, with disappointing results. Most of us,
generally, have an unwarranted optimism in the efficacy of new therapies
and it might represent, or be called, an optimism bias. This mental position,
with regard to a state of research in a specific field i.e. overactive
bladder therapy, has several serious implications. One is the creation
of potentially unrealistic expectations, for both patients and clinicians,
of the likely benefits of new treatments such as botulinum toxin. All
of us should make emerge a crucial empirical question: what is the prior
probability, on average, of a proposed new treatment for OAB or urge urinary
incontinence being superior to antimuscarinic agent treatments? The available
data seems to suggest that new treatments (vanilloids, nociceptin/orphanin
FQ, botulinum toxin) are equally likely to be inferior to standard treatments
as they are to be superior. The issue, which remains unsolved, is the
fact that new therapies are generally adopted in patients refractory to
anticholinergics and this represents a clear selection bias. Furthermore,
clinicians need to be aware that optimism is usually both unwarranted
and counterproductive when there is uncertainty about the long-term effects
of treatments, and of the resulting need to address this uncertainty in
clinical trials. On the contrary, in some circumstances it runs the risk
of deterring participation in clinical trials designed to reduce genuine
and important uncertainties about the effects of treatments, and of discouraging
replication of apparently promising early studies. Until these issues
are addressed there must remain doubts about whether clinicians involved
in trials, which use new drugs, are genuinely observing the outcome and
they maintain the ethical requirement of uncertainty.
authors have no conflict of interest. The authors perspective on this
topic is a personal one and of necessarily selective bibliography, and
cannot do justice to the vast literature about this field.
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June 16, 2006
Dr. Massimo Lazzeri
Department of Urology
Casa di Cura Santa Chiara Firenze,
Piazza Indipendenza 11, 50129, Firenze, Italy
Fax: + 39 05 548-0676