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
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