Transcript Slide 1

Painful bladder
(in women)
Professor Douglas Tincello
University of Leicester
Declaration of Interest
• Industry related 2012
– Honorarium for Allergan advisory board
– Honorarium, registration, accomodation for
Ethicon symposium at UKCS
– PI on RELAX study (onaBoNT-A)
• Independent funding
• All funding managed via University business
office
Tincello DG Kuwait Feb 16th -18th 2013
Hypotheses for aetiology?
• Four major theories
– Autoimmune disease
– Chronic infection
– Neurogenic inflammation
– Epithelial permeability
• None sufficient or totally convincing
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Bacteria
Viruses
“Toxins”
K+
Antiproliferative factor
?
Cytokines
Histamine
Mast cell
Substance P
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Complement
Antiproliferative factor
• APF similar to frizzled 8 protein-related
sialoglycopeptide (Keay J Urol 2005;173:909)
– G protein coupled receptor protein family
– ? Inhibition of proliferation signals
• Specific receptor identified (CKAP4/p63)
– Cytoskeleton associated receptor
– (Conrads et al J Biol Chem 2006;281:37836)
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Antiproliferative factor
• Urine of IC patients inhibits urothelial growth
– 86% of IC patient vs 12% cystitis vs 8% controls
– (Keay et al Urol 1998;52:974)
• APF produced by urothelium
– 19/20 bladder urine vs 1/20 renal pelvis urine
–
(Keay et al J Urol 1999;162:1487)
• 95% sensitivity; 94% specificity
– (Keay et al Urology 2001;57(6A):9)
• Irrespective of ethnic origin
– (Zhang et al Urology 2003;61:897)
Tincello DG Kuwait Feb 16th -18th 2013
Antiproliferative factor
• APF inhibits HB-EGF release from urothelium
• Exogenous HB-EGF blocks inhibition
– (Keay et al J Urol 2000;164:2112)
• Hyrdodistention causes APF ↓ & HB-EGF ↑
– (Keay et al J Urol 2000;163:1440)
• APF increases permeability of urothelium
–
(Zhang et al J Urol 2005;174:2382)
• Urothelial cells from IC patients grow slowly
–
(Keay et al Urol 2003;61:1278)
• Gene expression is “non proliferative”
– (Keay et al Physiol Genomics 2003;14:107)
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Antiproliferative factor
?
APF
Bacteria
Viruses
“Toxins”
K+
-
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HB-EGF
Diagnostic criteria…
• Interstitial cystitis (NIDDK criteria)
– Originally for research, but were adopted
– Tight, specific limits on functional volumes, cystoscopic
findings, symptom severity
– Comprehensive exclusion criteria
• IC/CPPS (Diokno A et al. Int J Urol, 10: S3, 2003)
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–
–
–
“Pain” includes: burning, pressure, discomfort
At least 3 months’ duration
May be exacerbated by intercourse
Patient must have frequency and urgency
Tincello DG Kuwait Feb 16th -18th 2013
…continued…
•
•
•
•
European Society for the Study of IC/PBS
Consensus statement June 2006
Stop using “interstitial cystitis”
“Bladder pain syndrome”
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–
–
–
Chronic pain related to bladder
Plus one other symptom
Exclusion of “confusable diseases”
Cystoscopy with hydrodistension and biopsy
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Confusable diseases
“The diagnosis
of a
confusable
disease does
not necessarily
exclude a
diagnosis of
bladder pain
syndrome”
A word about cystoscopy
• Cystoscopy is for excluding discrete pathology
– IC & sensory urgency have same leucocytes (Al Hadithi , 2002)
– Mast cells present in up to 40% of SU patients (Frazer, 1993)
– Glomerulations occur in normal bladders (Waxman, 1998)
– Symptoms not related to cystoscopic or urodynamic data
(Messing, Nigro; ICDB study, 1997)
• No longer a requirement for making a diagnosis
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Patients…
• Present with bladder pain ± other symptoms
• Pelvic pain can arise from several sources
– common autonomic/visceral pain pathways
– may be a common pathway for diverse initial insult
• Various “pseudonyms”
– urethral syndrome, sensory urgency, vulvodynia, myofascial
syndrome, endometriosis, “chronic pelvic pain”
• Management algorithm to screen for causes
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How I assess patients...
• Based upon:
– literature
Nordling J Eur Urol 2004;45:662
O’Leary MP Urol 1997;49:58
Daha LK J Urol 2003;170:807
– Learning from conferences
– clinical experience
Tincello DG Kuwait Feb 16th -18th 2013
Assessment-history
 Site, radiation and associations of pain
 Duration, and exacerbations in relation to urinary
symptoms (esp bladder filling)
 Presence, site and duration of dyspareunia
 post coital ache
 Frequency and nocturia
 Haematuria?
 ? Proven urinary tract infection
– including fastidious organisms
Tincello DG Kuwait Feb 16th -18th 2013
Assessment-examination
 Symphyseal tenderness, sacroiliac tenderness
– (pain on abduction of hips or limitation of ROM)
• Hyperaesthesia in lower abdomen/perineum
– (nerve entrapment)
 Vulval erythema or hyperalgesia on cotton swab test
in each quadrant of vestibule
 Palpate bladder base, pelvic muscles for tenderness
 (trigger points)
 reproduction of symptoms
 Cervical excitation, masses, endometriosis nodules
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Assessment-investigation
 Urine culture (including fastidious/anaerobes)
 3 day urinary diary
 frequency, nocturia
 daytime voided volumes vs waking void volume
• Urodynamics
– (sometimes)
• Double fill cystoscopy and hydrodistension
– (sometimes)
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Compare daytime
and waking
volumes
All vols usually
Day vols < 350ml
< 350mls
Waking vol > 350ml
Day vols include
>350 mls
PBS likely
PBS unlikely
PBS very
unlikely
Urodynamics ±
cystoscopy
Refer for bladder
retraining
UDS unlikely
to be useful
Urodynamics if
no better
Bladder drill +
PFE
Tincello DG Kuwait Feb 16th -18th 2013
Urodynamics
DO excluded
“PBS”
“Sensory urgency”
Sensation
Sensation
Capacity
Capacity normal
“Normal”
First sensation
<150 ml
First sensation
<150 ml
First sensation
≥ 150 ml
Capacity
<350 ml
Capacity ≥
350ml
(with coaxing!)
Capacity ≥
350 ml
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Treatment
• Specific treatment for specific conditions
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–
–
–
endometriosis
vulvodynia
myofascial syndrome/pelvic muscle trigger points
Sacroiliac or symphyseal joint pain
• PBS symptoms & normal bladder capacity
• PBS and reduced bladder capacity
Tincello DG Kuwait Feb 16th -18th 2013
Normal bladder capacity
• Bladder drill +/- diary to increase functional capacity
• Retrain sensations
• Anticholinergics may be of some benefit
– modulate sensation of urgency & discomfort?
• If no improvement…
– treat as if reduced capacity
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Reduced capacity
• “interstitial cystitis” or PBS
–
–
–
–
Quality of published work is poor
Most use NIDDK criteria (most severe patients)
Placebo effect is large
Few RCTs
• Pain control and patient support
• Intravesical therapy
• Oral therapy
• Recent systematic review (Giannantoni 2012 Eur Urol 61:29-53)
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Intravesical therapy
• Distension under GA for 10 minutes
– 55% response rate but transient
(Hanno 1991 Semin Urol 9:143; Pontari 1997 Urol 49 (5A):114)
• DMSO (Six to eight weeks of instillations 1-2/week)
– Response rate up to 90%; 40% relapse rate
– No RCT data
(Parkin 1997 Urol 49 (5A):105; Pontari 1997 Urol 49 (5A):114; Peeker 2000 J Urol
164:1912)
• Hyaluronic acid
– success rate of 30-70%
– One randomised trial, no placebo
(Kallestrup 2005 Scand J Urol Nephrol 39:143; Reidl 2008 IUGA J 19:717; Cervigni 2012
IUGA J 23: 1187; Yi-Song 2012 IUGA J in press; Lai M-C 2012 Int J Urol in press)
Intravesical therapy
• Botulinum toxin
– Mixed data from non –RCTs
– 75% improved at 3 months
• 80% fall in pain, 40% in frequency
– 75% relapse by 6 months
– RCT data (n=2) confirm efficacy
• Fall in pain and frequency @ 3/12
• Trigone injection shows greater effect
– 50% reduction in frequency & noturia
(Liu 2007 Urol 10:463; Kuo 2005 Urol Int 75:170; Smith 2004 Urol 64:871; Giannantoni
2008 J Urol 179:1031; 2010 Curr Drug Del 7:1; Kuo 2009 BJU Int 104:657; Pinto 2010 Eur
Urol 58; 360)
Oral treatments
• Cimetidine
– RCT of 400 mg significant reductions in pain and nocturia
(Seshadri 1994 Urol 44:614; Thilagarajah 2001 BJU Int 87:207)
• Pentosan polysulphate
– 3 of 5 RCTs show a difference
– 25%+ improvement in 25% vs 13%
(Parsons 1987 J Urol 138:513; Mulholland 1990 Urol 35:552; Parsons 1993 J Urol
150:845)
• Amitriptyline
– Success of 65-90% (Hanno 1994 Urol Clin N Amer 21:121; Pranikoff 2001
Urol 51 (5A); 179)
– Titration from 25mg nocte to 100mg
(van Ophoven 2004 J Urol 172:533)
Recent data
• Systematic review
– Giannantoni Eur Urol 2012;61:29-53
– 29 RCTs and 57 non random studies
– Standardised mean difference
• 0.8 = large effect
• 0.5 = moderate effect
– Assessed four outcomes
•
•
•
•
IC symptom index
Pain
Urgency
Frequency
IC symptom index
Pain
Urgency
Frequency
Conclusions...
• Cyclosporin A
– Effect on 3 of 4 outcomes (? Data)
• Amitriptyline
– Effect on all four outcomes
– 25mg – 100mg titrated at night
• PPS
– Limited efficacy
– Non-random studies suggest 50% long term effect
Giannantoni Eur Urol 2012;61:29-53
...cont’d...
• BCG
– Limited effect
– Concerns re use from cancer studies
• BoNTA
– Effective at pain relief
– ? Additional effect from trigone injection
• “The inability to propose definite conclusions
from the results coming from most of the
proposed treatments...”
Giannantoni Eur Urol 2012;61:29-53
History, exam,
MSSU, FV Chart
?
Day vols >350 mls
Bladder drill,
alkalinisation
Waking vol > 350ml
Specific
condition
identified
Treat
Y
All vols < 350mls
Better?
Disch’g
N
Normal capacity
Urodynamics
Reduced capacity
Intravesical Rx:
DMSO
BoNT-A
Oral Rx:
cimetidine
amitriptyline
Cystoscopy &
distension
Specific
condition
identified
Treat
Pain clinic