Saturday, July 20, 2013 • 1836—Parrish: “tic doloureux of the bladder”

Saturday, July 20, 2013
Robert J. Evans, MD, FACS
Associate Professor of Urology
Wake Forest University School of Medicine
[Inflammation 2nd]
“ulcers in the bladder sometimes occasion symptoms very
much like those of the stone…great care should be
taken not to mistake [this disease] for the stone…the
most certain method of determining this is
by…sounding…done 3 times but without finding any
stone after which Mercury was prescribed and the patient
soon after got well.”
•
•
•
•
•
•
•
--Notes of Wilmer Elmer,
1808-1810, Archives
of the Philadelphia College of
Physicians, page 388
1836—Parrish: “tic doloureux of the bladder”
1837—Mercier
1870—Tait
1887—Skene: “interstitial cystitis”
1907—Nitze
1914—Hunner
1987—NIH Workshop
!
“Non-cyclic pain of 6 or more months
duration that localizes to the anatomic
pelvis, abdominal wall at or below the
umbilicus, lumbosacral back or the
buttocks and is of sufficient severity to
cause functional disability or lead to
medical care.”
"
• CPP affects 9 to 15 million American women (~15% adult
female population)1
• Estimated to comprise ~15% of GYN referrals to
gynecologists2
• CPP is indication for ~18% of hysterectomies3
• More than 60% of diagnostic laparoscopies performed for
CPP reveal no evidence of pelvic pathology4,5
• Economic impact estimated at ~$3.3 billion per year1
• Prevalence is comparable to other chronic conditions
ACOG Practice Bulletin No. 51. American College of Obstetricians and Gynecologists.
Ob stet Gynecol. 2004;103:589-605.
Mathias SD, et al. Ob stet Gynecol 1996; 87:321-327. 2Walker EA et al. J Psychosom Obstet Gynecol 1991; 12(suppl):65-75. 3Gambone JC, et al. Fert Steril.
2002; 78:961-972; 4Levitan Z, et al. int GJ Gynecol Ob stet. 1985; 23:71-74. 5Kresch AJ, et al. Ob stet Gynecol. 1984; 64:672-674.
1
1
Saturday, July 20, 2013
Prevalence Rate per 1,000 Women
"
#
!
"
100
– 80% to 85% of women with unidentified etiology of
CPPS have pain of bladder origin1
– This translates into potentially >7 million women with
IC1
80
N=24,053
60
50
40
38
• IC is often misdiagnosed or under-diagnosed
– 38% of women scheduled for laparoscopy for
suspected endometriosis were cystosopically
confirmed to have IC2
21
20
10
41
37
30
CPP
Migraine
$
• IC may be a common cause of CPP
90
70
!
Asthma
Back Pain
• Consider pain of bladder origin: Interstitial
Cystitis
Cross-sectional analysis by UK Mediplus Primary Care database.
Zondervan KT et al. Br J Ob stet Gynaecol. 1999:106;1149-1155.
%
1
Parsons CL et al. Ob stet Gynecol. 2001;98:127-132.
2
Clemons JL et al. Ob stet Gynecol. 2002;100:337-341
&
'
!
• Oravisto, 1975: 18.6 per 100k females; 10.6 per 100k overall
• Held, et al 1990: 37 per 100k
• Curhan et al: 1999
– 750,000 women in USA (based on cystoscopic studies)
• Hanno et al: 1999
– 60% underdiagnosis rate
• Parsons et al: 2001
– 9 million women dx wrongly as Pelvic Pain of Gyn Origin
(
!
• Rand Corporation polled 100,000
households
• Validated Questionnaire
• 3 - 7.9 million women, ages 18 and up,
estimated to have Interstitial Cystitis
• Parsons and Dell, 2002, 2003: Using their findings IC could
actually be affecting
14 Million Women
!
• Category I - Acute bacterial prostatitis
• Category II - Chronic bacterial prostatitis
• Category III -Chronic Pelvic Pain Syndrome
(CPPS)
– Category IIIA - Inflammatory CPPS
– Category IIIB - Noninflammatory CPPS
CPPS
(nonbacterial
prostatitis/
prostatodynia)
95%
)
!
*
)
+
• Genitourinary/pelvic pain in the absence
of traditional uropathogens detected by
traditional culture techniques
• Pain for at least 3 of the last 6 months
• NIH exclusion criteria
• Voiding and sexual dysfunction
Krieger J, et al. JAMA. 1999;282:236
2
Saturday, July 20, 2013
)
(
)
!
!
•
Overall prevalence – 9%
•
+
• 90% to 95% of chronic prostatitis (CP) patients are urine
culture-negative2
Previous or concurrent diagnosis – 11% to
14%2
• 8% of men seen in urologic practices
were seen for the diagnosis of chronic prostatitis2
2 to 7 million visits/yr2,3
• Recurrent symptoms despite 6+ weeks of potent (but failed)
antibiotic therapies should raise IC suspicions
– 8% of urology visits
– 4th most common diagnosis at urology visits4
•
)
• 2 to 7 million annual office visits for prostatitis1
– Similar to ischemic heart disease and diabetes1
– More common than asthma
•
*
Is the real prevalence of IC in men 7-9 million??
– Levofloxacin (500 mg/d) vs placebo – no statistical difference3
– Ciprofloxacin (500 mg BID) W/wo tamsulosin (0.4 mg/d) vs.
placebo – no difference4
1
2
3
1Roberts
RO et al. Urology. 1998;51:578-584.
J Urol. 1998;159:1224-1228.
International Prostatitis Collaborative Network, Washington DC, Oct 2000.
4Schappert SM. National Center for Health Statistics Vital Health Stat, 13, 1994.
4
5
2Collins MM et al.
3Guschin Bl, Francis ME.
Gushchin BL et al. International Prostatitis Collaborative Network, Washington DC 2000.
Collins MM et al. J Urol. 1998;159:1224-1228.
Nickel JC et al. Urol 2003;62:614-617.
Alexander RB et al. Ann Intern Med 2004 Oct 19;141(8):581-589.
Forrest JB, et al. J Urol. 2004;172:2561-2562.
!
#
!
,
• Primary diagnosis of IC
)
Interstitial Cystitis
• Chronic Prostatitis (Chronic Pelvic Pain
Syndrome – NIH CPPS)
Chronic
Prostatitis
(95%)
Chronic
Bacterial Prostatitis
5%
What % of these
have IC?
-
CP/CPPS
• Voiding symptoms
• Frequency, urgency, nocturia
• Voiding symptoms
• Frequency, urgency, nocturia
• Pain with intercourse
• Pain with ejaculation, orchialgia
• Referred pain (lower abdomen,
urethra, lower back, medial
thighs, perineum, postvoid)
• Referred pain (urethral, perineal,
lower abdomen, testicular, scrotal,
rectal, postvoid)
• Pain on bladder filling
• Pain on bladder filling
• Nonrelaxing pelvic floor
• Nonrelaxing pelvic floor
• Diet can exacerbate Symptoms
• Diet can exacerbate Symptoms
Nickel JC et al. Can J Urol. 2000;7:1091-1098.
Forrest JB, et al. J Urol. 2004;172:2561-2562.
!
%
!
'
. %
• Among IC patients, the most common
previous diagnosis was UTI (19 of 45)1
!
"
IC
#
$%
&
&
$&&
'
1. Porru D et al. Int Urogynecol J Pelvic Floor Dysfunct. 2004;15:198-202. 2. Hanno PM. In: Campbell’s Urology.
Vol 1. 8th ed. Saunders; 2002:631-670. 3. Minaglia S et al. Urology. 2005;66:702-706. 4. Chung MK. JSLS.
2004;8:329-333. 5. Clemons JL et al. Obstet Gynecol. 2002;100:337-341. 6. Chung MK et al. JSLS. 2005;9:25-29.
7. McCormack WM. J Reprod Med. 1990;35:873-876.
• 60% of patients (18 of 30) with IC were
initially diagnosed with a UTI2
1. Driscoll A, Teichman JMH. J Urol. 2001;166:2118-2120.
2. Porru D et al. Int Urogynecol J Pelvic Floor Dysfunct. 2004;15:198-202.
3
Saturday, July 20, 2013
!
!
.
!
#
.
! ( !
• Pain may help differentiate IC from OAB1
– With OAB, urgency is associated with
fear of leakage2
– With IC, urgency is associated with pain2
• 96%
96% of patients (24
(24 of 25
25)) with detrusor
overactivity who were unresponsive to
anticholinergic medication were eventually
diagnosed with IC*†3
*Based on a positive Potassium Sensitivity Test (PST).
† Study included 47 patients diagnosed with detrusor overactivity.
1. MacDiarmid SA, Sand PK. Rev Urol. 2007;9(1):9-16. 2. Abrams P. Urology. 2003;62(suppl 5B):28-37.
3. Minaglia S et al. Urology. 2005;66:702-706.
• More than half of women treated for
endometriosis continued to experience
symptoms, including pelvic pain (N=24
(N=24))1
• 86%
86% of patients diagnosed with
endometriosis at a pelvic pain referral
center were also diagnosed with IC (115
(115 of
134))2
134
1. Dlugi AM et al. Fertil Steril. 1990;54:419-427. 2. Chung MK et al. JSLS. 2005;9:25-29.
!
!
.
/
!
• 79
79%
% of patients at a regional pelvic pain
center who suffered from persistent pelvic
pain (pre(pre- and postpost-hysterectomy) were
diagnosed with bladder dysfunction
consistent with IC (n=88
(n=88))1
• In a separate study of 45 women
scheduled
to undergo laparoscopy for CPP, 38
38%
%
were diagnosed with IC2
1. Chung MK. JSLS. 2004;8:329-333. 2. Clemons JL et al. Obstet Gynecol. 2002;100:337-341.
!
• IC and vulvodynia may have overlapping
symptoms due to a common etiology
• In a study of 46 women with IC or focal
vulvitis, 24% had both conditions1
1. McCormack WM. J Reprod Med. 1990;35:873-876.
"
Refractory Patients
New Patients
Recurrent UTI
Symptoms1
Urgency
(negative cultures)
Consider
IC
Unexplained
Pelvic Pain
(eg CP/CPPS)
1
2
3
4
Parsons CL et al. Female Patient. May 2002(suppl):12-17.
Chung MK et al. JSLS. 2002;6:311-314.
Miller JL et al. Urology. 1995;45:587-590.
Forrest JB, et al. J Urol. 2004;172:2561-2562.
Frequency
Pain
Symptoms With
Sexual Activity
INITIAL
SYMPTOMS
Dysuria
11%
Frequency
11%
Suprapubic discomfort 33%
Urgency
15%
Sexual dysfunction
0%
Nocturia
15%
Back, perineal,
7%
or scrotal pain
PREDOMINANT
SYMPTOMS
89%
85%
82%
82%
56%
45%
45%
Forrest JB, et al. J Urol. 2004;172:2561-2562.
Forrest JB, Quant V. Urology. 2001;57:26-29.
4
Saturday, July 20, 2013
0
,1
0
2
,1
3
IC May Be Misdiagnosed
• We may be missing millions of cases of IC in men and
women – Why?
• In women as:
• Waiting for severe vs early symptoms
–
–
–
–
• Thinking this is a disease that affects the middle aged
and it’s not
– Harvard Nurses’ Health Study
– Parson’s female medical student study
Recurrent UTIs
Overactive bladder (OAB)
Endometriosis
Dyspareunia
• In men as:
• Reluctance to consider using “therapeutic trial”
– Prostatitis
– Epididymitis
– Scrotal pain
– See failed therapy and consider new possibilities
Curhan GC. J Urol. 1999;162(2):500.
Parsons CL, Tatsis V. Urology. 2004;64(5):866-870.
Forrest JB, et al. Observations on the clinical factors affecting the treatment outcomes of interstitial cystitis. Poster presented at
the 11th Annual Scientific Meeting on Chronic Pelvic Pain; Chicago, Il; August 5-7, 2004.
!
.
!
#
Urothelial Dysfunction
(LUDE)
Irritating
Solutes
Mast Cell
Activation
GAG
Layer
Urothelium
Irritated
Nerve
C-fiber Nerve
Upregulation
Spinal Cord and Central
Nervous System
“Wind--Up”
“Wind
Inflammation
Visceral Organ Hyperalgesia/Allodynia
Urinary
Gynecologic
Pelvic Floor
Gastrointestinal
Sant GR. Rev Urol 2002. 4(suppl 1):S9-S15.
!
#
!!
'
Normal Urothelium
with Proteoglycans
K+ ions
!
Damaged
Urothelium
5
4
%
#
!!
Damaged Urothelium
with GAG “patch”
Urinary
Protease
Bladder
Lumen
Na-K Pumps
Depolarized
sensory neuron
Protected sensory neuron
Bladder
Muscularis
• Note heavy staining of umbrella cell layer
• Note staining of connective tissue underlying
urothelium
5
Saturday, July 20, 2013
.
6
! /
#
Bladder Injury
More Inflammation
Epithelial Layer
Dysfunction
Mast Cell Activation and
Histamine Release
Potassium Leak Into
Interstitium
Activation of CC-fibers and
Release of Substance P
•
•
•
•
•
•
APF increased (Keay, 2001)
GP51 glycoprotein (Byrnes, 1999)
Substance P increased (Pang, 1995)
Increased Kallikrein (Zuraw, 1994)
Altered GAG levels (Hurst, 1993)
Increased mast cell mediators (Theoharides,
1991)
• Increased norepinephrine (Stein, 1999)
• Tamm Horsfall Protein changes (Stein, 1993)
Adapted with permission from Evans RJ. Rev Urol. 2002;4(suppl 1):S16-S20.
#
• The prevalence of CPP of bladder origin – IC – is much greater
than previously believed in both men and women
,
Severity of Symptoms
• The proposed pathogenesis of IC is multifactorial
– GAG layer abnormality – seemingly the common denominator
– Mast cell activation – responsible for flares? Seasonal
Symptoms?
– Neural upregulation – especially in severe cases
• Early diagnosis of IC
(
– Can avoid unnecessary, inappropriate, and invasive treatment
(
)
+
*
.
%
)
/.
$
, $
$
– Can restore years of better QOL
– Might prevent prolongation and worsening of symptoms
%
!
(
7
Average Time Between Initial Development of
Symptoms and Diagnosis is 5 Years1
See at least
5 physicians
before diagnosis2
• Pelvic pain of unknown etiology
Diagnosis of IC
2-7 years4,5
May have
unnecessary
hysterectomy4
Teichman JM H. J Urol. 2001;166:2118-2120. 2Metts JF. Am Fam Physician. 2001;64:1199-1206.
al. Obstet Gynecol. 1994;83:556-565.
3Held PJ et al. In: Interstitial Cystitis. Springer-Verlag. 1990:29-48. 4Carlson KJ et
5M essing EM , Stamey TA. Urology. 1978;12:381-292.
• “Overactive bladder” that fails to
respond to anticholinergics
Significant suffering
and reduced QOL3
Initial
Development of
IC Symptoms
1Driscoll AD,
• “Recurrent UTI” that fails to respond
to antibiotics
• Chronic non-bacterial prostatitis/
prostadynia
Slide Courtesy of Grannum Sant, MD.
6
Saturday, July 20, 2013
6
! '
!
Common Causes of Flares
(primarily in women)
!
• Irritable bowel syndrome
• Vulvodynia/endometriosis
• Allergies
• Perimenstrual
• Fibromyalgia
• Sexual intercourse
• Migraine
• Diet
• Pelvic floor dysfunction
• Physical/Emotional Stress
• Recurrent UTIs
• Cystitis/vaginitis
• OAB refractory to anticholinergics
• History or suspicion of endometriosis
• Allergies
• Dyspareunia
• Premenstrual Pain/primary dysmenorrhea
/
!
Normal Subjects vs. IC Patients
Female
16
&
14
$
8
• Physical exam2
• Urinalysis and/or culture
6
• Urinalysis and/or culture
• Elective tests
4
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22
!"#$
%!"
> 8 – suspicious for IC
3
!
! .
)6
9
1
2
3
4
7-10
11-14
15-19
20+
2 a. How many times do you go to the bathroom at night?
0
1
2
3
4+
b. If you get up at night to go to the bathroom, does it
bother you?
None
Mild
Symptom Bother
Score
Score
Moderate Severe
Are you currently sexually active?
YES _____ NO_____
4 a. If you are sexually active, do you now have or have you
ever had pain or symptoms during or after
sexual activity?
b. If you have pain, does it make you avoid sexual activity?
Do you have pain associated with your bladder or in
your pelvis (vagina, labia, lower abdomen, urethra, perineum,
penis, testes, or scrotum?
6 a. When you have pain, is it usually
b. Does your pain bother you?
7 Do you still have urgency after you go to the bathroom?
8 a. If you have urgency, is it usually
b. Does your urgency bother you?
Never Occasionally
Usually
Always
Never Occasionally
Usually
Always
Never Occasionally
Usually
Always
Mild
Never Occasionally
! .
* . 6+
0
Moderate Severe
Usually
ICSI = Interstitial Cystitis Symptom Index.
PUF = Pelv ic Pain and Urgency/Frequency.
CPSI = Chronic Prostatic Symptom Index.
PPMT = Pre- and Post-Prostate Massage Test.
*%
Circle the answer that best describes how you feel for each question.
3-6
– PPMT
– Potassium
sensitivity test2
– Cystoscopy and
hydrodistention2
– Cystometrogram3
– Urine for cytology1
Hanno PM. In: Campbell’s Urology. 8th ed. WB Saunders Co; 2002:631-670.
Parsons CL, Parsons JK. Female Urology. 2nd ed. WB Saunders Co: 1996:167-182.
Parsons CL. Int J Urol. 1996;3:415-420.
%
8
1 How many times do you go to the bathroom during the day?
1
2
Parsons CL et al., Urology. 1991;37:207-212. Slide courtesy of CL Parsons, MD.
5 -
• Elective tests
– Potassium
sensitivity test2
– Cystoscopy and
hydrodistention2
– Cystometrogram3
– Urine for cytology1
2
5
– ICSI
– CPSI
– PUF2
• Physical exam2
10
3
• History1
– ICSI
– PUF2
%'
12
0
Male
• History1
'(
Always
Never Occasionally Usually Always
Mild
Moderate Severe
Never Occasionally Usually Always
SYMPTOM SCORE (1, 2a, 4a, 5, 6, 7a, 8a)
BOTHER SCORE (2b, 4b, 7b, 8b)
TOTAL SCORE (Symptom Score + Bother Score) =
)6 9
. 6
+
• Total scores range 1 to 35
• Correlates with PST and IC probability
• Validated (women > men) vs other A-P
conditions
• Healthy controls: < 2
• Scores:
– > 5: be suspicious
– > 10: highly suggestive (74%)
– > 20: highly indicative (90%)
Parsons CL, et al. Urology 2002;60:573-578
Total score ranges are from 1-35. A total score of 10-14 = 74%likelihood of positive PST; 15-19 = 76%; 20+ = 91% potassium positive
7
Saturday, July 20, 2013
. 6
!
4
Probability of IC (%)
% Potassium Positive
100
91%
74%
80
%
'
90%
Measure of Epithelial Permeability
76%
• Normal bladders do not absorb or react to K+
– KCl solution provokes no symptoms
60
• Epithelial dysfunction results in diffusion across the
interstitial barrier
40
– K+ stimulates sensory nerves • urgency or pain
20
0
0-4
n=56
5-9
n=20
10-14
n=61
15-19
n=114
20-24
n=75
Positive Response
25+
n=56
• No response to H20
• Grades response to KCl of at least 2 (0-5 scale)
PUF Score
N = 334 patients. 48 normals.
Parsons CL et al. Urology. 2002;60:573-578.
%
#
Drain Bladder
Insert #10
#10 French Pediatric
Feeding Tube
Solution 1
40 mL Water/Saline
!
!
• Detects abnormal bladder epithelial
permeability1
Solution 2
• Positive in 70% to 90% of IC patients
40 mL 0.4 M KCI
Slowly Infused Over
2 to 3 Minutes
No Immediate Reaction –
Allow to Remain 5 Minutes
Immediate Pain – Drain Bladder
and Wash With 60 mL H20
Rank Urgency (0(0-5)
Rank Pain (0(0-5)
Rank Urgency (0(0-5)
Rank Pain (0(0-5)
Positive Test
Drain Bladder
Drain Bladder
Instill Rescue Therapy
• 81% of gynecologic patients with pelvic pain
had increased potassium sensitivity3
• 84% of patients with prostatitis had positive
potassium sensitivity test results4
1
2
3
4
Parsons CL et al. J Urol. 1998;159:1862-1867.
Parsons CL et al. J Urol. 1998;159:1862-1867.
Parsons CL et al. Urology. 2002; 60:573-578.
Parsons CL et al. Am J Obstet Gynecol. 2002;187:1395-1400.
Parsons CL, Albo M. J Urol. 2002;168:1054-1057.
%
• Positive test indicates abnormal epithelial dysfunction
• (False) Positive test may result from:
– Bacterial cystitis
– Radiation cystitis
– Malignancy
• Negative test does not rule out IC (approx. 4 out of 5 patients
have a +PST)
• False negatives can occur
• Recent:
–
–
–
–
DMSO
Heparin
Hydrodistention
Pain medications
Consider Anesthetic Challenge
In Patients Who Present With
Significant Bladder/Pelvic Pain
• Maximally stimulated/severe sxs (Neural hyper-reactivity is
already MAXIMIZED…)
8
Saturday, July 20, 2013
0 .
Seen in ~ 10% of IC patients
6
*
6+
• Low molecular weight heat stable
• Produced in the bladder (not upper tracts)
• APF is present in 94% of IC patients and less than
10% of control patients with a variety of urogenital
disorders
%
• APF has been shown to normalize after
hydrodistention and sacral nerve stimulation
• APF is a potential exciting new marker for IC and
may be involved in the pathogenesis
of the disease
Keay S, et al. Urology. 2001;57(Suppl 6A):9-14
%
%
(
'
%
!
!
%
Pentosan
polysulfate
sodium
Bladder Insult
More injury
Epithelial Layer Damage
Mast cell activation and
histamine release
Antihistamine
therapy
Repair GAG layer and epithelial dysfunction
Potassium leak into
interstitium
Activation of C-fibers and
release of substance P
Slide courtesy of Robert J. Evans, MD
Tricyclic
therapy
9
Saturday, July 20, 2013
!
%
%
• Principles of Therapy
– Repair epithelial dysfunction
– Modulator neurogenic inflammation
– Stabilize mast cells
•
•
•
•
•
•
•
•
“Self-care”/conservative therapy
Oral medication
Intravesical therapy
Chronic pain management strategies
Pelvic floor rehabilitation
Neuromodulation
Hydrodistention
Surgical management
)#
.
!
. 6.
.
!
Interstitial Cystitis / Bladder Pain Syndrome
• An unpleasant sensation (pain, pressure /
discomfort) perceived to be related to the
urinary bladder, associated with lower
urinary tract symptoms of more than six
weeks duration in the absence of infection
or other identifiable causes
» Hanno and Dmochowski, 2009
)#
.
(
!
!
• Self report studies 850 / 100,000 women
• Clinical diagnosis 197 / 100,000 women
• IC/BPS symptoms 3.1 – 7.9 million women
)#
.
!
• Medline search 11/1/83 – 7/22/09
• 86 Treatment articles accepted for review
• Treatments rated A (High), B (Moderate),
or C (Low)
• Initial management strategies and
diagnosis based on expert opinion due to
insufficient peer-reviewed evidence
10
Saturday, July 20, 2013
)#
( !
.
!
.
!
• Careful H&P and labs to rule in symptoms that
characterize IC/BPS and rule out other
confusable disorders
• Baseline voiding symptoms and pain levels
should be assessed
• Cysto and/or urodynamics should be considered
as an aid to diagnosis for complex presentations
and are not required for uncomplicated cases
• KCL test not recommended
)#
.
!
.
• Grade A – Well conducted RCT or
exceptionally strong observational study
• Grade B – RCT with some weaknesses or
generally strong observational studies
• Grade C – Observational studies that are
inconsistent, have small sample size, or
have other problems
)#
)#
.
!
• Pain management should be continually
assessed for effectiveness
• IC/BPS Diagnosis should be reassessed if
no improvement after multiple treatments
• Standards – Directive statements that an action
should or should not be undertaken based on
grade A or B evidence
• Recommendations – Directive statements that
an action should or should not be undertaken
based on grade C evidence
• Options – Non directive statements where
balance between risk and benefit is unclear
)#
.
!
• Treatment should proceed using more
conservative therapies first, with less
conservative therapies employed if symptoms
are not controlled
• Multiple simultaneous treatments may be
considered based on baseline symptom
assessment
• Stop ineffective treatments after a clinically
meaningful interval has elapsed
)#
.
!
• Educate patient about IC/BPS including need for
multiple therapies
• Discuss self-care and behavioral modification
• Manual therapy techniques should be offered if
available. Pelvic floor strengthening is to be
avoided
• Implement stress management
• Initiate multi-modal pain management
11
Saturday, July 20, 2013
)#
5
.
!
! !
)#
.
• May present with a single symptom such
as dysuria, frequency or pain before
progressing to multiple symptoms
• Many comorbid conditions: Fibromyalgia,
IBS, CFIDS, Migraines, Vulvodynia
• Increased incidence of depression and
anxiety. Possible genetic linkage,
chromosome 13
•
•
•
•
Long-term antibiotics
BCG
RTX
High Pressure, long-duration
hydrodistention
• Long term steroids
%
%
Oral Therapy
Conservative Therapy
•
•
•
•
•
•
•
!
US FDA-approved:
Dietary modification
Bladder retraining
Behavior modification
Physical therapy
Herbal therapy
Biofeedback/electrical stimulation
Acupuncture
!
*
Dosage = 100 mg tid
Evolving Regimen: 200 bid
• Only oral treatment approved by the US FDA
for the relief of bladder pain or discomfort
associated with interstitial cystitis
• Relief may require at least 3 to 6 months of
continuous therapy for mild, 6-12 months for
moderate/severe
• Provides long-term improvement with
continued treatment
– Pentosan polysulfate sodium (PPS)
Off-label use:
–
–
–
–
–
–
–
+
Antihistamines
Antidepressants
Anticholinergics
Urinary analgesics
Narcotics/pain relievers
Gabapentin
Other
!
*
+
Side Effects (1% to 4%) – mild & transient
•
•
•
•
•
•
•
•
Alopecia, reversible upon discontinuation
GI — diarrhea, nausea
Headache
Rash
Dyspepsia
Abdominal pain
Liver function abnormalities (~ 1%)
Dizziness
Hanno PM. Analysis of long-term Elmiron therapy for interstitial cystitis. Urology 1997;49(Suppl 5A):93-99
Parsons CL. The therapeutic role of sulfated polysaccharides in the urinary bladder. Urol Clin North Am. 1994 Feb;21(1):93-100.
12
Saturday, July 20, 2013
)#
•
•
•
•
•
.
!
7 randomized trials, 500 patients
21-56% response rate
10-20% side effects
Grade B evidence
Option
!
!
%
Cystoprotek/Prostatoprotek
Cysta-Q/Prosta-Q
Glucosamine/Chondroitin/MSM
Natural Alternatives to Pentosan for GAG
replacement for patients unable to tolerate or
afford Pentosan
%
!
%
Indication
• Diet and Self Help
Treatment
Pathogenic Factor
Therapy
PPS*
+
Conservative Treatment
100 mg tid
200 mg bid (off label,
evolving)
Dose
Treatment of pain related to IC
Epithelial dysfunction
Pentosan Polysulfate
Neuromodulation
Antidepressants
Amitriptyline
25 mg qhs
Mast cell activation
Antihistamines
Moderate/severe anxiety; depression
associated with chronic physical
disease
Hydroxyzine
25 mg qhs or
25 mg qam and qhs
Management of allergic conditions
and histaminehistamine-mediated reactions
Symptomatic relief of anxiety
and tension
• Don’t withdrawal therapy when adding new
modalities
*PPS is the only FDA-approved oral drug for treatment of pain related with IC.
!
%
• GAG layer repair
– Pentosan Polysulfate 100 -200mg or
Heparin 20 – 40000 units can be instilled
daily, either alone or with an anesthetic
cocktail of lidocaine (10 cc 2%) plus
NaHCO3 (5cc) or marcaine(15 cc 0.5%)
!
%
• Tricyclic antidepressants
– Decrease pain
– Anticholinergic effect
– Anithistamine
– Sleep aid
• Amitriptyline 25 – 50 mg qhs
• Trazodone 25 – 50 mg qhs
13
Saturday, July 20, 2013
)#
•
•
•
•
•
•
.
!
1 randomized trial, 2 observational studies
25mg titrated to 100mg
65% response rate
79% report adverse event
Grade B evidence
Option
!
!
%
• Selective Serotonin Reuptake Inhibitor
(SSRI)
– Block reuptake of seratonin and
norepinephrine
– May not modify pain as well as tricyclic
• Paroxitine 10 – 40 mg
• Fluoxitine 10 – 40 mg
• Venlafaxine 75 – 300 mg
%
!
• Selective Norepinephrine Reuptake
Inhibitor (SNRI)
– Indicated for depression and chronic pain
management
• Duloxetine 30 – 120 mg daily
• Milnacipran 50 mg BID
%
Antihistamines
– Inhibits mast cell release of histamine
– Sedative
• Hydroxyzine 10 – 25 mg qhs
– May escalate up to 75 mg
• Ceterizine10 mg
– Non sedating
• Consider increasing dose to tid or qid during allergy
season
• Consider addition of H2 blockers especially in
patients with GI symptoms
)#
.
!
•
•
•
•
•
•
!
: ;
1 randomized trial, 1 observational study
23% response
92% response in patients with allergies
82% reported side effects
Grade C evidence
Option
)#
.
!
!
• 1 randomized controlled trial, 2
observational trials
• 400mg Bid
• Only 40 patients studied
• No adverse events
• Grade B evidence
• Option
14
Saturday, July 20, 2013
!
%
!
%
• Anticholinergics
• Mast cell stabilization
• Montelukast 10 mg daily
– May be used in addition to antihistamines
especially in patients with allergies or
asthma
!
•
•
•
•
•
•
•
•
Oxybutinin XR 10 - 30 mg
Tolterodine LA 4 mg
Darifenacin 7.5 – 15 mg
Solifenacin 5 – 10 mg
Trospium XR 60 mg
Fesoterodine 4 – 8 mg
Oxybutinin gel
Hyoscyamine
%
• Mirabegron 25-50 mg po qhs
• First Beta 3 agent
• Used for urinary urgency/frequency
when anticholinergics have failed
• No anticholinergic side effects
• May cause mild hypertension
!
– May help decrease frequency if pain is
controlled
!
• Urinary Analgesics
– May help diminish symptom flares and
exacerbations after instrumentation
-Freeze dried Aloe vera is a natural
alternative
Consider Prelief for food flares
%
Neuroleptics
!
− Requires slow dose escalation
− 100, 300, 400, 600, 800 mg tablets
• Topiramate 100 – 200 mg daily
• Pregabalin 50 – 75 mg TID
• Duloxetine 30 – 120 mg
%
• Alpha Blockers
Help to “down regulate” overly stimulated
spinal cord
• Gabapentin 100 – 3200 mg
%
– May help with dysfunctional voiding and
retention
•
•
•
•
•
Tamsulosin 0.4 mg daily
Alfuzosin 10 mg daily
Terazosin 5 – 10 mg daily
Doxazosin 4 – 8 mg daily
Silodosin 4 – 8 mg daily
15
Saturday, July 20, 2013
!
%
!
%
• Skeletal Muscle Relaxants
• Urinary Alkalinization
– Diazepam 2.5 – 10 mg tid
– Baclofen 10 mg bid
– Cyclobenzaprine 10 mg tid
– Tizanidine 4 mg daily
– Clonazepam 0.25 – 1 mg tid
– Carisoprodol 250 – 350 mg daily
– potassium citrate
• Will also have a sedative and anti
anxiety effect
• Valium vaginal Suppository 10 mg qd
!
%
!
• Narcotics and Pain Relievers
– Tramadol 50 mg q6h
– Hydrocodone and Oxycodone with low
Acetaminophen
– Oxycodone ER 10 – 80 mg bid – tid
– Methadone 10 – 20 mg q6h
– Morphine Sulfate ER 30 – 60 mg bid – tid
– Fentanyl transdermal 25 – 100 mg every 3 days
%
• Intravesical
– Dimethyl Sulfoxide (DMSO)
– Heparin or Pentosan Polysulfate
– Oxychlorosene Sodium Topical
– Silver nitrate
– BCG
• Avoid excessive use of breakthrough medication
• Direct patients with long term needs to a pain
clinic
• Pain contract and random testing
:!
• First/only agent approved for bladder
instillation
• Anti-inflammatory analgesic
• Muscle-relaxing properties
• Mechanism of action unknown
– Increases reflex firing of pelvic nerve
efferent axons
– Increases bladder capacity
#
!!
-
• In office or self-catheterization
• Treatments administered once/week or once
every other week
• Each treatment course = 6-8 weeks
• Procedure
– Insertion of catheter
– DMSO passed into bladder and retained for ~15
minutes
• Adverse Effects: Garlic-like taste/odor on
breath/skin
16
Saturday, July 20, 2013
<'
• Several agents shown to be effective:
• Heparin = mucopolysaccharide
– Lidocaine with NaHCO3 buffer1,2,3
– Beneficial anti-adherence action
– Heparin 10k - 40k units2
• Intravesical instillation
– PPS 100mg-300mg4,5
• Suggested regimen5:
• Trials indicate efficacy in symptomatic relief
and prolonged remissions of IC
– PPS 100mg or 40K units heparin in 8cc 1%-2%
lidocaine + 3cc 8.4% NaHCO3
1
2
3
4
5
)#
.
Heparin, Lidocaine, Bicarb
1 randomized trial
Several open label trials
Grade B evidence for Lidocaine, Grade C for Heparin
Option
)#
.
#
Nickel, JC. Rev Urol. 2002;4(3):112-121.
Moldwin RM, Sant GR. Clin Ob stet Gyn. 2002;Vol. 45(1):259-272.
Henry R, et al. J Urol. 2001;165:1900-1903.
Bade JJ, et al. BJU. 1997;79:168-171.
Parsons CL. Contemp Urol. Feb. 2003;15(2):22-35
!
• DMSO
• 2 randomized crossover trials
• Grade C evidence
•
•
•
•
•
=
!
:
• 6 observational studies
• High initial efficacy of 74-86% at 3 months
• Symptoms indistinguishable from baseline
at 1 year
• Grade C evidence
• Option
)#
.
!
•
•
•
•
•
•
1 randomized trial compared to PPS
3mg/kg in 2 daily doses
75% response rate
38% report > 50% decrease in frequency
94% adverse event
2 observational studies report significant pain
relief in 91%
• Grade C evidence
• Option
)#
5
.
!
!
• 3 studies
• 66% of patients report clinically significant
improvement in pudendal study
• 94% report improvement in bladder
capacity, frequency, voided volume,
nocturia, and pain
• Grade C evidence
• Option
17
Saturday, July 20, 2013
.
%
Surgical
• URINARY
– Urinary analgesics, anticholinergics, neuromodulation
• Hydrodistention
• Ablation of ulcers
• Neurostimulators
• PSYCHOSOCIAL
– Antianxiety, antidepressants, psychotherapy
• ORGAN CONFINED
– PPS, antihistamines, instillations
• INFECTIOUS
– implantable
– percutaneous
– Antibiotics
• NEUROLOGIC / SYSTEMIC
• Augmentation cystoplasty (not recommended)
• Cystectomy/Urinary diversion (rarely indicated)
– Antidepressants, neuroleptics
• TENDERNESS
– Muscle relaxants, physical therapy
"
(
Refractory Patients
• Nursing staff
Overactive
Bladder
Treatment
Failures1
Invest time with patient at first office visit
Clearly outline expectations for the patient
Patient education tools
Patient support groups
Failed
Endometriosis
Therapy1,2
Urgency
Consider
IC
Frequency
Pain
- Dyspareunia
Nonbacterial
Prostatitis3
– Interstitial Cystitis Association (ICA) 800-HELP-ICA
– Interstitial Cystitis Network (ICN) 707-538-9442
1
2
3
>3
New Patients
Recurrent UTI
Symptoms1
– Handles 90% of telephone calls
– Performs routine procedures
(eg, urinalysis, urine C + S, potassium sensitivity
test, intravesical treatments)
•
•
•
•
5 %
Parsons CL et al. Female Patient. May 2002(suppl):12-17.
Chung MK et al. JSLS. 2002;6:311-314.
Miller JL et al. Urology. 1995;45:587-590.
6
• Hx of “chronic UTI’s” since age 16
• Response to abx variable
• Cultures rarely obtained and only 2 grew
uropathogens
• Hx of “tight urethra” Dilated x5
• Hx of “endometriosis” based on symptoms but
laparoscopy showed “scar tissue”
• Currently complains of frequent urgency,
abdominal pain, back pain, trouble voiding,
nocturia and has not had intercourse in 3 years.
• Marriage in trouble.
18
Saturday, July 20, 2013
•
•
•
•
•
•
•
•
•
Chronic UTIs as a child
Difficulty toilet training
History of constipation, possible IBS
Migraines
Pain in extremities: “I think I have fibro”
Trouble sleeping: “I think I have chronic fatigue”
Hypertension
Hypothyroid
Depression
• Surgery
– Appendectomy
– Cholecystectomy
– Hysterectomy
• Imaging
– CT: normal
– Pelvic and Abdominal Ultrasound: normal
• Cysto: “They told me it was normal, but it hurt like hell.”
• UDS
–
–
–
–
–
No incontinence
First sensation 37 cc
Max capacity 122 cc
No instability
Stop/Start Uroflow with straining
• FH
(:
– MGM: “Took to her bed because of cystitis”
– Sister: fibromyalgia
• SH
–
–
–
–
Diet: Follows IC diet, but it has not helped
ETOH: Stopped
Tobacco: Trying to quit
Exercise: None
• Positive Findings
– TMJ Syndrome
– 14+ trigger points
– Back pain over sacrum
– Abdominal pain and distention
– Normal urethra, tender bladder, pain in vagina
at 5 and 7 o’clock
• ROS
– 14 point ROS performed and all organ systems
positive
• Questionnaires
–
–
–
–
PUF: 29
ICSI: 12
ICPI: 12
VAS: 9.5
Voiding Diary: 28 voids, Nocturia x5, no incontinence
!
! ,
•
•
•
•
•
•
Interstitial Cystitis
Pelvic Floor Dysfunction
Fibromyalgia
IBS
Anxiety
Depression
19
Saturday, July 20, 2013
!
The basic assessment should include a
careful history, physical examination, and
laboratory examination to document
symptoms and signs that characterize
IC/BPS and exclude other disorders that
that could be the cause of the patients
symptoms.
Clinical Principle
!
Cystoscopy and/or urodynamics should be
considered when the diagnosis is in doubt;
these tests are not necessary for making
the diagnosis in uncomplicated
presentations.
Expert Opinion
!
Initial treatment type and level should
depend on symptom severity, clinician
judgment, and patient preferences;
appropriate entry points into the treatment
portion of the algorithm depend on these
factors. Counseling patients with regard to
reasonable expectations for treatment
outcomes is important.
Clinical Principle
!
Baseline voiding symptoms and pain
levels should be obtained in order to
measure subsequent treatment effects.
Clinical Principle
!
Treatment strategies should proceed using more
conservative therapies first with less
conservative therapies employed if symptom
control is inadequate for acceptable quality for
life; because of their irreversibility, surgical
treatments (other than fulguration of Hunner’s
lesions) are generally appropriate only after
other treatment alternatives have been
exhausted or at anytime in the rare instance
when an end-state small, fibrotic bladder has
been confirmed and the patient’s quality of life
suggests a positive risk-benefit ratio for major
surgery.
Clinical Principle
!
Multiple, concurrent treatments may be
considered if it is in the best interest of the
patient; baseline symptom assessment
and regular symptom level reassessment
are essential to document efficacy of
single and combined treatments.
Clinical Principle
20
Saturday, July 20, 2013
!
Ineffective treatments should be stopped
once a clinically-meaningful interval has
elapsed.
Clinical Principle
!
The IC/BPS diagnosis should be
reconsidered if no improvement occurs
after multiple treatment approaches.
Clinical Principle
!
First Line Therapy
Self-care practices and behavioral
modifications that can improve symptoms
should be discussed and implemented as
feasible.
Clinical Principle
!
Pain management should be continually
assessed for effectiveness because of its
importance to quality of life. In pain
management is inadequate, the
consideration should be given to a
multidisciplinary approach and the patient
referred appropriately.
Clinical Principle
!
Patients should be educated about normal
bladder function, what is known and not known
about IC/BPS, the benefits vs. risks/burdens of
the available treatment alternatives, the fact that
no single treatment has been found effective for
the majority of patients, and the fact that
acceptable symptom control may require trials of
multiple therapeutic options (including
combination therapy) before it is achieved.
Clinical Principle
!
First Line Therapy
Patients should be encouraged to
implement stress management practices
to improve coping techniques and manage
stress-induced symptom exacerbations.
Clinical Principle
21
Saturday, July 20, 2013
!
Second Line Therapy
Appropriate manual physical therapy techniques
(e.g., maneuvers that resolve pelvic, abdominal
and/or hip muscular trigger points, lengthen
muscle contractures, and release painful scars
and other connective tissue restrictions), if
appropriately-trained clinicians are available,
should be offered. Pelvic floor strengthening
exercises (e.g., Kegel exercises) should be
avoided.
Clinical Principle
!
Second Line Therapy
DMSO, heparin, or lidocaine may be
administered as second-line intravesical
treatments.
Options
!
Second Line Therapy
Amitryiptyline, cimetidine, hydroxyzine, or
pentosan polysulfate may be administered
as second-line oral medications
Options
!
Third Line Therapy
Cystoscopy under anesthesia with short
duration, low-pressure hydrodistension may be
undertaken.
Option
If Hunner’s lesions are present then fulguration
(with laser or electrocautery) and/or injection of
triamcinolone should be performed
Recommendation
!
Fourth Line Therapy
A trial of neurostimulation may be
performed and, if successful, implantation
of permanent neurostimulation devices
may be undertaken.
Option
!
Fifth Line Therapy
Cyclosporine A may be administered as
an oral medication if other treatments have
not provided adequate symptom control.
Option
22
Saturday, July 20, 2013
!
!
Fifth Line Therapy
Intradetrusor botulinum toxin A (BTX-A)
may be administered if other treatments
have not provided adequate symptom
control. The patient must be willing to
accept the possibility that intermittent selfcatheterization may be necessary post
treatment.
Option
Sixth Line Therapy
Major surgery (substitution cystoplasty,
urinary diversion with or without
cystectomy may be undertaken in carefully
selected patients for whom all other
therapies have failed.
Option
!
! !
- ! ,
• Treatments that should not be offered:
– Long term antibiotics – Standard
– BCG – Standard
– RTX – Standard
– High Pressure Long Duration Hydrodistension
– Recommendation
– Long Term Steroids – Recommendation
%
• IC Diet
• Multi modal medications
– Pentosan Polysulfate 200 mg po bid
– Hydroxyzine 25 mg – 50 mg po qhs
– Amitriptyline 25 mg – 50 mg po qhs
• Anesthetic cocktail daily
– Heparin 40,000 unit, Lidocaine 2% 10 cc, Sodium
Bicarb 8.4% 5 cc
• Pelvic Floor Rehab
– Biofeedback, E-Stim, and Myofascial release
• Valium Vaginal Suppositories 10 mg daily
3
-
•
•
•
•
•
•
Patient feels she is “some better”
Instillations help, but her urethra hurts
Sleeping better
Pentosan helps, but “can not afford it”
Xylocaine Jelly 2% or ointment 5%
Consider Gabapentin, Pregabalin or SNRI
for pain management
• Consider anti anxiety agent
• Consider Cysta Q or Cystoprotek
23
Saturday, July 20, 2013
?
-
@
• Patient is better, but intercourse is still
painful
• Bladder pain less, but levators still tight
• Trigger point injections performed with
significant relief
• Tramadol for pain
• Careful consideration given to use of
narcotics
7
•
•
•
•
-
• Medications, instillations, physical therapy,
have eliminated 80% of her pain
• Still unhappy with frequency and
dysfunctional voiding
• Proceed to Interstim trial
– PNE vs. staged implant
– Indications: urgency frequency, urge
incontinence, retention
-
Patient doing well
Still has seasonal allergy flares
Pain after intercourse
Patient still uses instillations weekly,
especially after intercourse
• There is hope for even the worst patient with IC
and pelvic pain
• Proper characterization of the patients pain is
essential
• All pain triggers must be treated aggressively
• Work with the patient and use trials of different
treatments to develop an individualized program.
• AUA guidelines are an essential tool for
diagnosis and management of IC/BPS
24
`