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University of Michigan Health System Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS): My Approach to Patients after 25 years of Practice

Jane L. Miller, MD, FPMRS Associate Professor of

University of Washington Medical Center Seattle, WA University of Michigan Disclosures Health System l Jane L. Miller, MD, FPMRS

NIH Study Investigator – MAPP

University of Michigan Health System AUA Guidelines Definition IC/PBS

• “an unpleasant sensation (pain, pressure, discomfort) perceived to be related to the , associated with lower urinary tract symptoms of more than six weeks duration, in the absence of infection or other identifiable causes.”

• Agreed upon by Society for Urodynamics and Female Urology (SUFU) University of Michigan Health System Etiology

• Unknown

• Theories – Infection (Chronic or Recurrent) – Autoimmunity – Abnormal activity – Deficient bladder glycosaminoglycan (GAG) layer – Inhibition of urothelial cell proliferation University of Michigan Health System AUA IC/PBS Guidelines

AUA Guideline for the Diagnosis and Treatment of Interstitial Cystitis/Bladder Pain Syndrome Hanno, P et al. J Urol 2011

Diagnosis and Treatment of Interstitial Cystitis/ Bladder Pain Syndrome: AUA Guideline Amendment Hanno, P et al. J Urol 2015

Complete guideline: www.auanet.org/guidelines AUA Guidelines for IC / BPS

University of Michigan Health System University of Michigan Conceptualizing IC/BPS Health System (Guidelines)

• Primary bladder disorder vs secondary?

– Bladder pain disorder that is often associated with voiding symptoms and other systemic disorders.

• Member of a family of hypersensitivity (dysregulation) disorders that affect somatic/visceral organs?

• Part of the continuum of painful vs. nonpainful syndrome? University of Michigan Health System Conceptualizing IC/BPS

• Urothelial dysfunction (secondary to infection, autoimmune disease, trauma, etc)

• Visceral pain syndrome/neuropathic

• Central pain syndrome with voiding symptoms Basic Assessment University of Michigan Health System • History • Frequency/Volume Chart • Physical Exam • Post-void residual • Urinalysis, culture • Cytology, if smoking history • Symptom Questionnaire/Pain evaluation: -O’leary Sant ICSI and ICPI index, Pain visual analog, pain body maps Diagnostics to consider in University of Michigan Health System “complicated” IC pts

• Urine cytology • Imaging • – Not diagnostic, may help direct tx if Hunner lesions present • Urodynamics (floro) • Laparoscopy • Specialized referral University of Michigan Cystoscopic/Urodynamic Health System Findings Cystoscopy: -Glomerulations are not diagnostic -Hunner’s ulcers: inflammatory area or ulceration

Urodynamics: -no agreed upon criteria for IC/PBS, may provide information on voiding symptoms -with floro-, reflux, etc University of Michigan Health System Glomerulations University of Michigan Health System Hunner’s Lesions

University of Michigan Health System Hunner’s Lesions

University of Michigan Health System Ulcer vs Nonulcer IC/BPS

• Hunner’s ulcers are not ‘ulcers’ – Pale lesion with surrounding erythema, bleeds/ ruptures with distention

• Comprise 10-40% of IC/BPS – 10% - U.S. – 40% - Europe University of Michigan AUA Guidelines Health System Clinical Management Principles

• Treatments ordered from most to least conservative • is appropriate only after all else exhausted, except in treatment of Hunner’s ulcers, rare cases of small fibrotic bladder and severe detriment to QOL. • Initial treatment level depends on symptom severity, clinician judgment and pt. preference • Multimodal therapy may be considered • Ineffective treatment should be stopped • Pain management should be considered throughout course of therapy to maintain function and minimize pain • Diagnosis should be reconsidered if no improvement AUA Guidelines University of Michigan Health System First-Line Treatments

• Patient Education – Normal bladder function, info about IC/BPS, expectations, ICA

• Self-care / Behavioral Modification – Avoid activities, foods, drinks which worsen sxs – Urge suppression

• management / Relaxation

• Pain management AUA Guidelines University of Michigan Health System First-Line Treatments

• Behavioral modification may improve symptoms in some patients -fluid decrease or increase -Application of local heat to bladder/perineum -Avoidance of bladder irritants -Meditation -Pelvic floor muscle relaxation/urge suppression -Optimzing bowel function -OTC meds 45% of pt did behavior mod before meds had mod to marked improvement in symptoms Foster, J et al J Urol 2010 AUA Guidelines University of Michigan Health System Second-Line Treatments

• Pelvic floor PT – Including appropriate manual techniques – Evidence strength from C to A • Oral Agents – , , , (Elmiron) • Intravesical Agents – Intravesical agents • DMSO, , • Multimodal Pain Management – Pain mgmt alone not enough. Treat bladder related sxs, stress University of Michigan Amitriptyline-Elavil Health System

• TCA with anticholinergic activity • Blocks NE and serotonin reuptake • Several studies show response rates of greater than 55% in treated patients (tolerated greater than 25mg) – 10mg titrate to 50 mg – Contraindicated in pts with long QT or conduction block or other arrythmias – 63% response rate

» Foster et al, J Urol 2010 University of Michigan Health System Second Line Therapies

• Hydroxyzine (C) – 25-50mg, 23-92% response, ?

• Cimetidine (B) – 300mg BID 44-57% response University of Michigan Pentosan polysulfate Health System

• Heparin analogue in oral form – Based on GAG permeability theory

• Meta-analysis concluded that there is evidence to support efficacy – Parsons (1993): PPS group: 32% vs. 16% placebo – Ave voided vol increase-20cc, no other obj improvement – Contradictory results – Hunner disease likely not as responsive

• Possible side effects – Reversible alopecia – Elevated LFTs – Diarrhea, nausea/vomiting – Increased bleeding risk (rare) University of Michigan Health System Dimethylsulfoxide (DMSO)

• Solvent -- product of the wood pulp industry

• FDA approved

• Limited data to support its efficacy

• Deemed safe

• Various treatment regimens – Commonly described as weekly for 6 weeks – Cocktails – 61-90% response-variable f/u University of Michigan Health System AUA Guidelines Third-Line Treatments

• Cystoscopy with Hydrodistention (C) – Under anesthesia – Low pressure / short duration distention: 60-80 cmH2 – Response: 30-54% at 1 mos-7%at 6 mos

• Treatment of Hunner’s lesions (C) – Fulgaration: 75% improve/resolved 24 mos – injection (60mg/tx session) – Data demonstrates significant sx improvement

• Pain Management Cysto with Hydrodistention University of Michigan Health System

• Not standardized, but general anesthesia recommended

• Hunner’s ulcer – can be fulgerated

• Glomerulations – nonspecific finding

• Can result in symptom improvement but typically only transient

• Measure Capacity <200cc is considered a poor prognostic sign AUA Guidelines University of Michigan Health System Additional Treatments

-Fourth-line – (intradetrusor injection) (C) • Moved from 5th to 4th line • 100 units same as 200 units with fewer AE, often combined with hydrodistension • 73% at 1 mos, 38% at 6 mos, baseline 1 yr --Sacral Neuromodulation (C) -staged best, pain at battery site – Pain Management AUA Guidelines

University of Michigan Health System • Fifth-line – Cyclosporine A (oral) • 85% response rate in Hunner’s ulcers pts • 30% if no Hunner’s • If drug stopped symptoms return • Side effects (30-55% pts)include: HTN, elevated creat, gross hematuria, facial hair growth, gingival hyperplasia, alopecia, mouth ulcers, cutaneous lymphoma, gout – Forest JB Jurol Oct 2012

To be offered by experienced providers University of Michigan AUA Guidelines Health System Additional Treatments

• Sixth-line – w/ or w/out – Augmentation Cystoplasty after supratrigonal cystectomy Patients must understand that symptom relief is not guaranteed-pain can persist, esp in nonulcer IC/PBS. – Pain Management

For patients with end-stage structurally small bladders, diversion/substitution is indicated at any time clinician and patient believe appropriate. University of Michigan Health System AUA Guidelines Treatments that should not be offered • Long-term

• Intravesical BCG

• Intravesical

• High-pressure, long-duration hydrodistention

• Systemic long-term oral – -efficacy was high but side effects high – Short term for flares OK AUA Guidelines for IC / BPS

University of Michigan Health System University of Michigan Health System Assessment-What I Do

• Detailed history-hour visit • GU exam-localization of pain, pelvic floor • Imaging: if hx/PE/labs warrant, if no symptom improvement, if never been done • Voiding diary • ?pain diary-sometimes • Pain scale • IC questionnaires-only if required by studies • Cystoscopy-usually in OR, not responding or pt in need of reassurance or concerned about Hunner’s lesions/ contracted bladder University of Michigan Health System Urinary Frequency

• Why do you urinate so often? • What happens if you get stuck in traffic and can’t get to the bathroom? • One management option for patients with frequency is to purposely delay voiding/retrain their bladder. Patient response to this “I couldn’t because of pain” “ I couldn’t because I would leak” ” I could do it but it might be annoying.” University of Michigan Health System Pain

• Where? – Why do you think it’s your bladder? • When did it start? • Inciting event? • H/O sexual abuse? • Characterize: achey, crampy, burning, radiating, intermittent? • Exacerbating/alleviating factors? – Diet, sex, menstrual cycle, physical activity, position, traveling in a car? University of Michigan Health System “IC” patients I have Cured (or patients I’ve seen who needed further evaluation) • GU atrophy • TB • Intravesical calcified foreign bodies – Mesh complications • Urethral diverticulum • Ureteral stone-distal / • Eosinophilic cystitis University of Michigan Health System University of Michigan Health System My IC Patient “Phenotypes”

• I Adult Dysfunctional Elimination Syndrome • II Pelvic floor hypertonus/myalgia • III Post-uti hypersensitivity • IV Classic IC/bladder hypersensitivity • V Hunner’s lesions/contracted bladder • VI Chronic pain syndrome-generalized University of Michigan Health System Adult Dysfunctional Elimination Syndrome

• Younger “IC “ patient • Hx: childhood enuresis, childhood utis, +/-urge incontinence, urinary hesitancy with delay in voiding, painful urgency, lifelong constipation • Exam: pelvic floor hypertonus, dysynergic puborectalis • Diagnostics: Floro-urodynamics, CT-IVP or renal u/s and KUB • TX: OAB, pelvic floor hypertonus, constipation University of Michigan Health System Pelvic Floor Hypertonus

• C/O “something falling out”, “deep pressure”, “bowling ball in my ” • Hx: trauma/sexual abuse, anxiety, back pain, positional pain/worse sitting, no dietary sensitivities, heat/warm baths helpful • EXAM: pain reproduced on palpation of pelvic floor, decreased ROM • TX: PT, trigger point/Botox injections, muscle relaxants, vaginal valium, heat/ice University of Michigan Health System Post-UTI Hypersensitivity

• C/O constant bladder awareness/irritation rather than pain • HX: + bacterial culture, symptoms present for less than a year, often able to sleep thru the night • EXAM: awareness reproduced on palpation of bladder base • TX: education/reassurance, bladder retraining, phenazopyridine/uribel, low dose TCA, UTI prevention (vaginal estrogen in menopausal women) • Sx’s resolve, but seem to be at risk for recurrence University of Michigan Health System Classic IC

• C/O Small void frequency day and night, pain worse with bladder filling and some improvement with voiding • Hx: often diet sensitivities, , hormonal exacerbation, flares • Exam: pain reproduced on palpation of base of bladder/bimanual • Tx: Guidelines, vaginal estrogens University of Michigan Health System Hunner’s Lesions/Contracted Bladder

• Pt’s often over 40, men (selection bias) • Hx: very small volumes day and night, pain if holds, but often largely pain free after voiding, +autoimmune disorder, renal disease, hematuria • Exam: often no pain on pelvic exam • Diagnostics: floro-urodynamics, upper tract imaging, cystoscopy/hydrodistension • Tx: NSAIDs/?oral steroids, Instillations including steroid, cyclosporine, hydrodistension with steroid injection (kenalog), cystectomy University of Michigan Health System Chronic Pain Syndrome

• Multiple pain sites/syndromes • Tx: systemic therapies, pain management clinic, counseling/PCP AUA Guidelines for IC / BPS

University of Michigan Health System University of Michigan Health System Classic IC

• C/O Small void frequency day and night, pain worse with bladder filling and some improvement with voiding • Hx: often diet sensitivities, dyspareunia, hormonal exacerbation, flares • Exam: pain reproduced on palpation of base of bladder/bimanual • Tx: Guidelines, vaginal estrogens University of Michigan IC/PBS:”My Guidelines” Health System Impressions after 25 years of treating IC patients

First Line Treatment -Try to put their history, exam findings, etc together to explain how/why they may have developed IC with present theories -Symptom control may require multiple therapeutic interventions: “something for the nerves, for the muscles and for the bladder lining” -Pelvic floor PT (+mindfulness training) consider early if appropriate -Counseling -Prelief trial if significant dietary sensitivities -Lab slips, specimen cups-urine cult –no appt. University of Michigan IC/PBS:”My Guidelines” Health System Impressions after 25 years of treating IC patients Second Line Treatment

-Know your PT, if pt tried before and didin’t work, ask what was done-NO KEGEL’S -Nortriptyline seems to be better tolerated with fewer side effects. -If unable to tolerate TCA’s consider gabapentin or lyrica for neuropathic pain University of Michigan IC/PBS:”My Guidelines” Health System Impressions after 25 years of treating IC patients Second Line Treatment

– Bladder instillations: • Generally don’t use DMSO-side effects • Heparin, lidocaine, sodium bicarbonate, prednisone, +/-gentamycin • Pt. taught to do at home – Hormone manipulation • Vaginal estrogen for post-menopausal pt • Continuous OCPs for pts with cyclical flares University of Michigan IC/PBS:”My Guidelines” Health System Impressions after 25 years of treating IC patients

Third Line Treatment

Cystoscopy/Hydrodistention: -30cc of 1% lidocaine and 60mg B&O supp at end of case -Measure bladder capacity with distension -Pt’s with smaller bladder capacities tend to have more symptomatic improvement University of Michigan IC/PBS:”My Guidelines” Health System Impressions after 25 years of treating IC patients

Fourth Line Treatment

-Neuromodulation -Have not found it to be helpful for pain, but for frequency -Botox -Not many pts because of insurance and ISC concerns University of Michigan IC/PBS:”My Guidelines” Health System Impressions after 25 years of treating IC patients

• Fifth Line Treatments

– Pain Management • B & O suppositories, lidocaine instillation for flares • Role for narcotics • Pain Specialists: refer anytime, but especially when regular use of narcotics being considered University of Michigan IC/PBS:”My Guidelines” Health System Impressions after 25 years of treating IC patients

Sixth Line Treatments -Simple cystectomy with diversion -supratrigonal cystectomy with augmentation will have to perform ISC -diversion only: leave bladder still have “bladder pain”, pyocystis -Frequency will be better, but no guarantee of pain improvement -Pts with bladder capacities ~250 cc or less on hydrodistenstion (keep in mind poor compliance and renal injury), Hunner’s ulcers have more pain relief.

University of Michigan Health System Encourage your patients to participate in studies

• MAPP 2 (NIH)