What to know about treating Interstitial cystitis/Painful bladder syndrome

Casey Kowalik, MD Kansas University Medical Center Department of Urology Assistant Professor

No disclosures

What to know about treating Interstitial cystitis/Painful bladder syndrome

Objectives❑ Initial evaluation of IC/BPS ❑ 4 phenotypes ❑ Treatment algorithm based on phenotype ❑ When to refer

Clinical diagnosis• Lower urinary tract symptoms

– Ex. frequency, urgency

• Pain, pressure, or discomfort in the pelvic area – Ex. with bladder filling, relieved by bladder emptying

– Ex. dysuria

– Ex. ejaculatory pain

• Present for at least 6 weeks • Negative urine culture

AUA guidelines International Continence Society

URINARY symptoms• Frequency, nocturia

– Voids/day: 16.5 (IC) vs. 6.5 (normal)

• Urgency – Anesthetic bladder capacity: 575 mL (IC) vs. 1100 mL

(normal)

• Hematuria

Wide range of PAIN symptoms• Suprapubic pain • Pelvic pain • Vaginal pain • Urethral pain • Dysuria • Pain with bladder filling

(relieved with emptying)

• Quality • Location • Duration • Severity • Anything help? • What makes it worse?

Symptoms• Flares • Diet • Stress • Several questionnaires available

Have you noticed a relationship between anything you eat and your symptoms?

• NIH Chronic Prostatitis Symptom Index (men only)

F:M 5:1 Up to 1.9% of men Median age of 40

Berry et al J Urol 2011 Suskind et al J Urol 2013

Pathophysiology

Further evaluation– History of recurrent UTIs, STIs

– Prior pelvic surgery

– Neurological conditions

Physical exam– Pelvic exam

• External genitalia

• Bladder base in females

• Urethra

• Pelvic floor muscles

Pelvic exam• Sensory function of pudendal nerve

– Light and sharp touch on labia or penis/scrotum

• Motor function of pudendal nerve – Voluntary pelvic floor contraction

Physical exam– Pelvic exam

– Back exam

• Spinal abnormalities

• CVA tenderness

– Abdominal exam

• Suprapubic tenderness common

– Neurologic exam

Initial diagnostic work up• Labs

– Urinalysis – Urine culture

Treatment• Validate “I believe you are having these symptoms”

Treatment• Validate “I believe you are having these symptoms” • Set expectations early • Multimodal therapy

– From most to least conservative

• If no improvement, re-evaluate the diagnosis

Initial treatment for ALL patients

• Patient education • Dietary modification • Stress management

– Exercise/yoga, meditation/mindfulness, therapy

4 Phenotypes

Pelvic floor dysfunction

Painful urgency

Central sensitization syndrome

Hunner's ulcers

1

2

3

4

Case #1• 21y female presenting with urethral pain and burning

with urination. • Frequency about every 3 hours during the day. No

nocturia. +urgency. • She has had vaginal intercourse once, but it was so painful

she hasn’t done it again. • She has a BM every 4-5 days and this is “normal” for her

Case #1 (cont.)

• Normal external genitalia • Contracted, tense muscles

– “High tone”

• Tender to palpation

Case #1 (cont.)

• Urinalysis and urine culture negative

Case #1 (cont.)

PLAN?

• Pelvic floor physical therapy – NOT Kegels (Should be avoided!)

– Get buy-in from the patient • 59% patients diagnosed with IC/BPS with symptom

improvement – Men too!

• Study of 384 men diagnosed with chronic prostatitis, pelvic floor tenderness noted in 50%

Pelvic floor dysfunction

Polackwich et al Prostate Ca and Disease 2016 Fitzgerald et al J Urol 2012

• DRE is not only about the prostate

Pelvic floor PT- What can the patient expect?

• Manual therapy techniques (internal and external) • Trigger point release • Connective tissue manipulation • Neural mobilization and stretching

• If nervous system’s movement and elasticity are impaired, the symptoms may arise from neural tissues

• Biofeedback for muscle retraining • Lifestyle and activity modifications • Therapeutic pain neuroscience education

Unlike other treatments, where a pill is the same no matter where it is prescribed, one must be careful to ensure the physical therapy is of high quality and of the correct type. If practitioners are going to be treating patients with CP/CPPS, a good relationship with a knowledgeable physical therapist is necessary for success.

Resources: http://aptaapps.apta.org/DirectoryofCertifiedSpecialists/default.aspx https://pelvicrehab.com

• Pelvic floor physical therapy • Trigger point injections • Acupuncture

• Vaginal valium – Intra-vaginal 10mg suppository

– No great data to support its use with a negative small trial

– Anecdotally works well just before pelvic floor physical therapy to relax pelvic muscles in those with high-tone

– Available at compound pharmacies

Pelvic floor dysfunction

• Pelvic floor physical therapy • Trigger point injections • Acupuncture

• Vaginal valium • Transvaginal estrogen 3 nights per week

– Estrace 0.01% – Premarin

Pelvic floor dysfunction

Case #2• 73yF presenting with a complaint that “I can tell my bladder is always there” every

since she had a urinary tract infection about 7 months ago. • Urinary frequency every hour and urgency, nocturia x3. Occasional small volume

urgency incontinence. • Since her initial UTI, she has been treated with multiple courses of antibiotics with

some improvement in her symptoms while taking, but has immediate return of symptoms when stopping.

• In the past 3 months, have you had a feeling of a strong urge or feeling that you had to urinate or “pee” that made it difficult for you to wait to go to the bathroom?

• If yes, would you say this urge is mainly because of – Pain, pressure, discomfort – Afraid won’t make it to the bathroom in time

– Both

– NeitherRICE questionnaire. RAND Interstitial Cystitis Epidemiology Study.

Case #2 (cont.)

Case #2 (cont.)• Pain worsens with a full bladder. Improves slightly about 10

minutes after voiding. • She has stopped drinking soda • Has not really paid attention to foods as related to her

symptoms

• Physical exam – Tearful – Abd- soft, tenderness to palpation of suprapubic area

but no peritonitis, no masses

– Pelvic exam- vaginal atrophy, tenderness to bladder and urethra, otherwise normal

Case #2 (cont.)

• Negative urinalysis and urine culture

Case #2 (cont.)

PLAN?

Painful urgency

• IC diet • **Prelief** • Pelvic floor physical therapy • Oral therapies

Oral Therapies• Amitriptyline 25-75 mg qHS • Cimetidine 400 mg BID • Hydroxyzine 10-50 mg qHS • Pentosan polysulfate 100 mg TID • Gabapentin 300-2100 mg TID

Amitryptiline• MoA: Tricyclic antidepressant • Rationale: decreases neuropathic pain, decreases

urgency/frequency (Ach effect), *nocturia* • Dose: response rate 66%+ at 50 mg+ qHS, but half of

patients can’t tolerate • Side effects: fatigue, constipation, dry mouth dizziness,

somnolence

Foster et al J Urol 2010

Cimetidine• MoA: H2 histamine receptor antagonist • Rationale: blockage of mast cell histamine release • Dose: 400 mg BID showed significant improvement in

suprapubic pain and nocturia compared to placebo – Thilagarajah et al BJU Int 2001

• Side effects: No major noted

Hydroxyzine• MoA: H1 receptor antagonist • Rationale: blockade of mast cell histamine release • Dose: I usually start with 10mg qhs (up to 25-75 mg qHS) • Side effects: sedation, GI upset • Best results in patients with allergic phenotype • RCT showed best results when given in combo with

pentosan polysulfate

Sant et al J Urol 2003

Pentosan Polysulfate (PPS)• MoA: Heparin analogue, structurally similar to glycosaminoglycans • Rationale: re-establish GAG layer function, decrease K+ leak • FDA approved • Dose: 100 mg TID • Side effects: headache, GI upset, rash, reversible alopecia (5%) • Maximum effect takes up to 6 mo • From pooled data 50% of patients have a 50% reduction in

symptoms, most recent RCT showed no difference between PPS and placebo at 24 weeks

• ?Risk of retinopathyNickel et al J Urol 2015 Hwang et al Urology 1997

Gabapentin• MoA: anticovulsant, GABA analogue • Use : inhibit neural upregulation and neurogenic spinal

cord inflammation • Dose: 300 mg -2100 mg divided TID • Side effects: sedation • Option for patients with neuropathic pain • Monitoring: careful dose titration to balance sedative

properties • Only one trial looking at its use alone found 48%

improvement in pelvic pain

Sesaki et al Tech Urol 2001

Painful urgency

• IC diet • **Prelief** • PFPT • Oral therapies • Bladder instillations

Bladder instillations• Catheter inserted per urethra in sterile fashion • Instill “cocktail” into the catheter • Catheter removed • Patient asked to hold the solution for 30 minutes and rotate

around every 10 minutes

• Warn patients that their symptoms may worsen for the initial 24 hours but then should improve

• Weekly x 6

Bladder instillation “cocktails”• Dimethysulfoxide (DMSO)

– FDA approved – Organic solvent with anti-inflammatory and analgesic properties – Strong data to support its use with 50% improvement

• Perez et al J Urol 1988 – 50 mL solution of 50% DMSO, 30-60 min dwell time once weekly for 6

weeks – Side effects: garlic breath (halitosis), flare after 1st instill, UTI

• Heparin – GAG analogue – No systemic absorption – 20-40,000 IU diluted in 10 mL NS

• Lidocaine – Better absorbed when alkalinized with Na Bicarb

• Pentosan polysulfate (Elmiron) – Only 1-3% of oral PPS reaches bladder – Small RCTs showed improvement compared to oral – 300 mg in 50 mL of NS twice weekly for 6 weeks

Ingredients References

20 mL 0.5% bupivacaine, 20 mL 2% lidocaine jelly, 40 mg triamcinolone, 10–20 000 IU heparin, 80 mg gentamicin

Moldwin217

8 mL 2% lidocaine, 4 mL 8.4% NaHCO3, 20 000 IU heparin

Welk and Teichman123

50 mL 0.5% bupivacaine, 50 mL 8.4% NaHCO3 (8.4%), 100 mg hydrocortisone, 10 000 IU heparin, 80 mg gentamicin

Lukban et al.218

40 mL 0.5% bupivacaine, 10 000 IU heparin, 2 mL dexamethasone, 20 mL NaHCO3

Mishra219

50 mL DMSO, 44 mEq (1 amp) NaHCO3, 10 mg triamcinolone, 20 000 IU heparin

Hanno220

300 mg pentosan polysulfate sodium, 10 mL 2% lidocaine, 10 mL 4.2% NaHCO3; add to this sufficient NaCl 0.9% to reach a total volume of 60 mL

Bade219

40 000 IU heparin, 8 mL 1% (80 mg) or 2% lidocaine (160 mg), 3 mL 8.4% NaHCO3 suspended in a volume of 15 mL total fluid

Parsons120

50 mL DMSO, 100 mg hydrocortisone, 10 mL 0.5% bupivacaine, 5 mL NaHCO3 (Optional: add heparin)

Payne219

5 mL 4% lidocaine followed by 5 mL 8.4% NaHCO3

Nickel et al.150

Painful urgency

• IC diet • Prelief • Pelvic floor PT • Oral therapies • Bladder instillations • Hydrodistention • Pain management referral

• NEVER narcotics

Hydrodistention

• Despite lack of randomized data one of the most commonly performed treatments

• Performed under anesthesia with pressures of 80 cm H2O for 5 minutes and repeat

• Visualization of glomerulations are non-specific

• Short lived symptom relief (<6 mo)

Painful urgency

• Pain symptoms • IC diet • Prelief • Pelvic floor PT • Oral therapies • Bladder instillations • Hydrodistention • Pain management referral

• Urinary symptoms • Bladder training

• Urge suppression (“quick flicks”) • Medications

• Antimuscarinics • Mirabegron

Treatment considerations: Urinary urgency• Medications

– Antimuscarinics • Non-selective for M3 receptor

• Selective for M3 receptor

– β3 Agonists

Neural regulation- Storage

Ach M2, M3

Adapted from Campbell-Walsh Urology Fig 69-30

Pelvic nerve: S2, 3, 4 Parasympathetic

Sacral spinal cord

NE β 3

Hypogastric nerve: T10-L2 Sympathetic

Ach + ⍺1

Antimuscarinic medications• MoA: inhibits muscarinic receptors in detrusor to prevent contraction • Side effects: dry mouth, constipation, dry eyes, rare urinary retention

• Non-selective for M3 – Oxybutynin (oral and transdermal)- usually start with 10mg XL daily – Tolterodine – Fesoterodine – Trospium 20 mg BID – Solifenacin

• Selective for M3 – Darifenacin

Treatment considerations: Urinary urgency

β3 Agonists• MOA: stimulates β3 receptors in the detrusor muscle to

inhibit contraction • Side effects: hypertension, nasopharyngitis, headache,

rare urinary retention

• Mirabegron 25-50mg po daily

• Can be used in combination with anticholinergic medications

Treatment considerations: Urinary urgency

Painful urgency

• Pain symptoms • IC diet • Prelief • Pelvic floor PT • Oral therapies • Bladder instillations • Hydrodistention • Pain management

• Urinary symptoms • Bladder training

• Urge suppression (“quick flicks”) • Medications

• Antimuscarinics • Mirabegron

• Onabotulinum toxin A • Neuromodulation

• PTNS • Sacral/Interstim

Onabotulinum toxin A• Proposed to cause afferent desensitization by inhibiting

efferent release of Ach • 100 to 200 units injected into the bladder • RCT showed 72 % vs 48% success rate 100 U and 200 U

+ HD, with more adverse events with 200 U • Retreatment common by 9-10 mo with continued response • Does not appear to be effective for patients with Hunner’s

lesions • Low but potential risk of urinary retention

Kuo et al BJU Int 2009 Pinto et al J Urol 2013

Sacral Neuromodulation• Not approved by FDA for treatment of IC/

PBS • No RCTs have been completed to assess

effect in patients with IC/BPS • Recent meta-analysis of 583 patients

showed 84% success rate including decreased pelvic pain, nocturia, frequency, urgency and increased average voided volumes

• Side effects include painful stimulation, battery side pain, lead migration

• Surgical revision rate of 27-50%

Wang et al Sci Rep 2017

Peripheral tibial nerve stimulation (PTNS)

• IC diet handout • Prelief • Oxybutynin XL 10 mg daily • Estrace 0.01% M/W/F evenings • Follow up in 6 weeks

Case #2 (cont.)

PLAN?

• 73yF with bothersome lower urinary tract symptoms and pain with bladder filling

• Pain only happens when she “cheats” the diet • Takes prelief as needed • Didn’t tolerate side effects of oxybutynin but the frequency

and urgency are less bothersome now • She has resumed sexual activity and “loves” the estrace

Case #2 (cont.)

• But what if she wasn’t better? - No difference with the diet or prelief - Oxybutynin helped her frequency and urgency - Pain is still there

Case #2 (cont.)

• Do I have the correct diagnosis?

Oral Therapies• Amitriptyline 25-75 mg qHS • Cimetidine 400 mg BID • Hydroxyzine 10-50 mg qHS • Pentosan polysulfate 100 mg TID • Gabapentin 300-2100 mg TID

Case #3• 45yF with PMH significant for fibromyalgia and migraines

presenting with “pelvic pain” which has been ongoing for last 3 years. She is s/p hysterectomy/BSO for endometriosis a year ago but this did not improve her pain. She also has bothersome urinary frequency and urgency. Denies urinary incontinence.

• BM every 2-3 days • Always had dyspareunia

Central sensitization syndromes

• Fibromyalgia • Irritable bowel syndrome • Chronic fatigue syndrome • Migraines • Endometriosis • Vulvodynia

Overactive bladder IC/BPS

Urinary symptoms

Pain

Either* 95% CI Both* 95% CI Odds Ratio Odds Ratio Irritable bowel syndrome ROME

3.0 1.4, 6.1 3.5 1.2, 9.8

Chronic pelvic pain 3.3 1.2, 9.0 4.5 1.2, 16.3TMJ disorder 6.7 1.9, 23.9 9.1 2.0, 41.4 β coefficient β coefficient PROMIS Pain intensity 2.96 0.63, 5.28 6.52 2.76, 10.28Somatic symptom score 1.55 0.07, 3.03 2.97 0.58, 5.36*Neither was the reference category

Relationship between painful urgency and painful filling

Oral Therapies• Amitriptyline 25-75 mg qHS • Cimetidine 400 mg BID • Hydroxyzine 10-50 mg qHS • Pentosan polysulfate 100 mg TID • Gabapentin 300-2100 mg TID

Central sensitization syndromes

• Stress reduction • Symptom based treatments • Oral therapies • Pain management referral

Case #4• 65y male, current smoker, presents with reports of pain in the lower

abdomen and at the tip of penis that started 3 years ago but has been worsening over the last 3 months. The pain is severe and is limiting his daily activities.

• He has urinary frequency every 45 mins to hour and nocturia x4. • He had an episode of prostatitis 2 years ago that was treated with a

prolonged course of antibiotics which only minimally helped his symptoms.

• He has noticed blood in his urine a time or two. • No prior bladder or urethral surgery. • No STIs

Case #4• PMH:

– Hypertension

• Medications – Tamsulosin 0.4mg qhs

Case #4 (cont.)• Physical Exam: • Very fit, healthy, appears younger than

age • Seems anxious • Abdomen: soft, non distended, non

tender • DRE: increased sphincter tone, smooth,

small prostate, Obturator internus and levators tender to palpation

Case #4 (cont.)• Urinalysis with 10 RBCs/hpf • Urine culture negative • CT urogram is negative for cause of gross hematuria

• Refer to Pelvic floor physical therapy • Discuss starting OAB medication • Refer to Urology for cystoscopy

PLAN?

Cystoscopy- Hunner’s ulcer

https://www.youtube.com/watch?v=lp-SRQIO2y8&t=21s

Hunner’s ulcers

• Men have a higher prevalence of Hunner’s ulcers • Treatment:

• Fulguration • Injection with triamcinolone

• Series have shown 90% response • About 50% will have recurrent ulcerations over 2

years

Hellesohn et al Urol 2012

Hunner’s ulcers

• Repeated fulguration/injection • Cyclosporine A 2mg/kg

Cyclosporine A

• MoA: inhibits calcineurin -> suppressing T cell activation • Rationale: immunomodulator that suppresses bladder

inflammation • Dose: 2 mg/kg divided twice daily (max 300 mg daily, start

100 mg BID for 1 mo then decrease to 100 mg daily) • Option for patients with Hunner’s lesions (68% response

vs 30% in non-Hunner’s) • Side effects: HTN, renal insufficiency • Monitoring: blood pressure, creatinine, CyA levels

Hunner’s ulcers

• Repeated fulguration/injection • Cyclosporine A 2mg/kg • ?Hyperbaric oxygen • Cystectomy

Conquering IC/BPS

Overview of treatments• ALL patients

– Patient education

– Dietary modification

– Stress management • Exercise/yoga, meditation/mindfulness, therapy

• Which phenotype(s) do they fit?

Overview of treatmentsPainful urgency

• Pain symptoms • IC diet • Prelief • Pelvic floor PT • Oral therapies • Bladder instillations • Hydrodistention • Pain management referral

• Urinary symptoms • Bladder training • Medications

• Antimuscarinics • Mirabegron

• Onabotulinum toxin A • Neuromodulation

• Pelvic floor physical therapy • Trigger point injections • Acupuncture

• Vaginal valium • Transvaginal estrogen

Pelvic floor fPainful urgencyPelvic floor dysf

Overview of treatments

Hunner’s Pelvic floor fPainful urgencyCSS

• Repeated fulguration/injection

• Cyclosporine A 2mg/kg • ?Hyperbaric oxygen • Cystectomy

• Stress reduction • Symptom based treatments • Oral therapies • Pain management referral

Do not offer these treatments• Long-term antibiotics • Oral steroids long-term

American Urological Association Guidelines

Consider Urology referral when…• >3RBCs/hpf on urinalysis or gross hematuria • Pelvic organ prolapse • Recurrent UTIs • Male incontinence • Severe incontinence • Neurologic disease • High post void residual • Behavioral and medical treatment not sufficient

Additional testing• Urodynamics • Cystoscopy • CT urogram • Prostate volume

Key messages• Syndrome of lower urinary tract symptoms + pain, present

for >6 weeks with negative urine culture • Set treatment expectations

– Multimodal approach to treatment, multiple concurrent treatments, most to least conservative

– Multi-disciplinary

– Goal of restoring daily life

• Which phenotype? • Periodically re-evaluate diagnosis

Clinical Interests

• Pelvic organ prolapse • Overactive bladder • Urinary incontinence • Neurogenic bladder • Bladder reconstructive surgery

Casey Kowalik Email: ckowalik@kumc.edu Office phone: 913-588-0799 Cell phone: 603-305-3082

Clinic locations: Overland Park KU Hospital

Contact info

Questions?

Resources for the Office and Patients• Hanno PM, Burks DA, Clemens JQ et al. American

Urological Association Guideline: Diagnosis and treatment Interstitial cystitis/Bladder pain syndrome. 2014. www.auanet.org

• Locate pelvic floor physical therapists – https://pelvicrehab.com/ – https://ptl.womenshealthapta.org/