Pelvic Pain

From the University of California San Diego School of Medicine’s Urology Postgraduate Course

C. Lowell Parsons, MD, Professor of Surgery and Urology, University of California, San Diego, School of Medicine

Educational Objectives

The goal of this program is to improve the diagnosis and management of interstitial cystitis (IC). After hearing and assimi­lating this program, the clinician will be better able to:

1.   Diagnose IC based on symptoms and a simple patient history.

2.   Explain how diseases of the bowel may share a potassium-related etiology with IC.

3.   Discuss the role of healthy mucus in protecting the bladder and bowel.

4.   Recognize symptoms of overactive bladder or urethral syndrome that may be caused by IC.

5.   Provide treatment that allows patients immediate relief from symptoms of IC.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the plan­ning committee to disclose relevant financial relationships within the past 12 months that might create any personal con­flicts of interest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Parsons is a consultant-lecturer for OrthoMcNeil. The planning committee reported nothing to disclose.

Acknowledgments

Dr. Parsons was recorded at 2nd Annual UCSD Urology Postgraduate Course, held February 19-20, 2009, in La Jolla, CA, and sponsored by the Division of Urology and the Moores Cancer Center, University of California, San Diego, School of Medicine. The Audio-Digest Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.

Pathophysiology and Diagnosis of Interstitial Cystitis

Background on interstitial cystitis (IC): epithelial dysfunction  —  primary pelvic disease process generating uri­nary urgency, frequency, pain, and incontinence in men and women; patients with classic form of IC typically have severe form; onset in patient’s youth associated with long-term bladder deterioration and eventual IC, chronic pel­vic pain syndrome, or painful bladder syndrome; underappreciated features  —  IC represents continuum of mild to severe disease; disease process begins with upregulation of sensory fibers (urge fibers and pain fibers); affects blad­der muscle; afferent (sensory) nerves  —  function as protective mechanism by encouraging voiding in response to full bladder or pathogens; physicians may focus on efferent nerves and not on afferents, ie, neutralize sensory nerves without regard for their protective function; epithelium of bladder  —  regulates homeostasis, ie, interactions between metabolites and toxins contained in urine and bladder muscle and nerves; glycosaminoglycan (mucus) layer  —regulates epithelial permeability

Protamine sulfate: study in rodents  —  protamine causes equivalent injuries to mucus layer in humans and animals; urea movement monitored via radioactive tracers in isolated rodent bladders and Ussing chambers; treated bladders showed selective injuries (produced by adhesion of cationic drug to anionic mucus) and marked increases in permeability; treat­ment with heparinoids (eg, pentosan polysulfate [Elmiron]) or heparin reversed majority of mucus layer injury; function of mucus  —  electronegative characteristics of healthy mucus attract water; water entrapped near bladder surface creates physical barrier against movement of solutes; study of protamine in humans  —  large doses caused marked movement of urea across epithelium (consistent with urinary leakage); treatment with heparin for 30 min reversed effects (indicates efficacy of heparinoids in treatment of disease processes that causes pathologic changes to bladder mucus)

Bladder absorption: healthy bladders do not absorb urea (absorption increases to 25% after injury); bladders of pa­tients with IC typically absorb 27% of urea (increases with Hunner's ulcers caused by severe late-stage disease pro­cesses); potassium  —  urinary toxin; successful elimination essential; urinary concentration varies from 25 to 125 mEq/L (extremely toxic); 8 to 9 mEq/L capable of depolarizing muscles and nerves (sustained depolariza­tion leads to necrosis); mucus prevents migration of potassium; secondary-defense hypothesis  —  if potassium en­ters interstitium, lymphatic fluid and blood vessels under epithelium allow rapid recycling of potassium into blood; hypothesis of potassium-related pathologies  —  bladder and bowel both handle extreme concentrations of potas­sium; common symptoms and characteristics shared by bowel and bladder diseases may be caused by potassium in­creases during urinary holding phase; potassium enters prostatic ducts and urethra during voiding (ie, process affects bladder and urethra); potassium and protamine study  —  0.4 M solution of potassium infused through blad­der catheter; protamine-induced injury to bladder mucus layer significantly increased absorption; treatment with heparin reduced absorption; reaction not seen in control group receiving sodium instead of potassium; potassium sensitivity test (PST)  —majority of literature indicates positive rate of »80%; controls found negative in 4 trials; rel­atively sensitive and specific test, indicating abnormal epithelial permeability; protamine-like substances  —  possible cause of mucus pathologies; ie, cations normally present in urine (often protein metabolites [especially with diamine cations]); have low affinity for electronegative compounds at bladder surface; gradual injury to blad­der leads to potassium cascade (and numerous associated pathologies); inflammatory mediators  —  present in active phase of disease (nearly absent in mild phases)

Toxins in urine: antiproliferative factor (APF)  —  no specific APFs implicated in IC; not yet successfully isolated from human urine via mass spectrometry; study of protamine as model positive control  —  unknown component of urine induces toxicity in bladder epithelium; protamine utilized as positive control to mimic endogenous toxic fac­tors; isolated fractions of urine from healthy patients; treated cells in culture with protamine (kills them); isolated fractions of treated urine then taken via dialysis, with molecular weight cutoffs at 500 daltons (Da), 1000 Da, and 3500 Da (compounds clustered at 500-1000 Da, indicating low molecular weight); weighted fractions of urine then exposed to heparin-agarose beads (affinity chromatography); elution of beads with water yielded toxic urine with affinity for heparin

Tamm-Horsfall protein (THP): humans produce »50 mg daily; found in all vertebrates; no confirmed explanation of biologic role; speaker’s hypothesis  —  protein functions as “albumin of urine” (richly sialated electronegative molecule capable of scavenging and protein-binding toxic factors in urine (ie, protective urinary macromolecule); studies of toxic factor neutralization  —  majority of studies conducted with healthy participants (patients with IC show 2-3 times as many toxic factors); THP-neutralized toxic factors found to kill cells in cultures (comparable to results seen with pentosan polysulfate and possibly induced by similar mechanism); samples of THP taken from patients with IC less effective at neutralizing toxic factors (compared to THP from healthy patients); sialic acid im­parts THP’s electronegativity and biologic activity; desialation strips THP of its properties; THP in controls vs pa­tients with IC  —  no difference in levels of protein; however, protein samples taken from patients with IC showed significantly lower levels of sialic acid, so THP abnormal in patients with IC

Pathogenesis: speaker’s hypothesis  —  defective THP allows increase in unbound urine cations or toxic factors; cat­ions and toxic factors bind to and deactivate function of mucus on bladder surface; increased permeability due to damaged mucus allows potassium to enter interstitium (begins disease process); progression  —  insidious; begins with increased urinary frequency and leads to escalating pain cycles; hypothesis explains clinical picture, eg, how disease develops, how it recovers, successful therapies

Questions and Answers

Progression, remission, and comorbidities: asymptomatic patients may not show symptomatic progression after discontinuing therapy for short periods; children of patients with IC may inherit genes for defective THP (increases risk for IC); earliest diagnosis made at 2 to 4 yr of age; »20% of adult sufferers presented with urologic symptoms in childhood; pregnancy  —  causes remission of IC in 80% of women (possibly due to 3- to 4-fold increase in THP); hormones may also affect sialation (possibly explains symptoms associated with menstrual cycle); irritable bowel syndrome  —  strong association with IC (possibly due to similar concentrations of potassium in bowel and bladder); speaker speculates histamine and allergies make epithelium leak and may link both diseases; in animal models, pro­voking nerves of colon produces reaction in bladder

Diagnosis: speaker asserts diagnosis may be established with brief patient history and analysis of urine; IC causes in­continence in »20% of patients (due to potassium stimulating sensory nerves or directly depolarizing bladder mus­cle); frequency primarily bladder symptom (often mistakenly treated as prostate symptom in men); 75% of patients eventually develop urethral symptoms (eg, dysuria); pain  —  in speaker’s experience, many patients do not report exacerbated bladder pain during emptying; patients often present with chronic pelvic pain (occurs anywhere be­tween navel and knees, anteriorly or posteriorly); may present as isolated flank pain on right side, scrotal pain on right side, labial pain on right side, or testalgia; typically focuses between pubic bone and rectum (in patients of both sexes); speaker rejects theories conflating IC with painful bladder syndrome, and argues overactive bladder should not be treated as IC without pain; infections  —  IC often misdiagnosed as recurrent bladder infections in women (in speaker’s experience, premenopausal women do not often develop >2 bladder infections in 2-3 yr [more than 2-3 “bladder infections” per year indicates nonbacterial problem]); in men, majority of primary care physi­cians and urologists misdiagnose IC symptoms as prostatitis and treat with antibiotics (treatment costs $1.5 billion annually); exacerbation of IC  —sexual activity associated with flares; often occurs 1 wk before menstrual period; associated with mast cell activation caused by seasonal allergies; urethral syndrome  —possible early stage of IC (indicated by comparable [but less significant] response to PST); PST in prostatitis  —healthy patients show no re­sponse to potassium (confirmed by multiple studies); endometriosis and yeast vaginitis  —  frequently misdiagnosed in women with IC; with complaints of burning or itching, insignificant quantities of yeast may be taken as evidence for vaginitis; often diagnosed without assessing quality of life and symptoms; serial analysis of gynecologic patients  —included 12 to 15 million women with pelvic pain; all patients given PST and urologic symptom ques­tionnaire; 81% had positive PST; pain masks urgency and frequency; all patients with endometriosis or vulvar ves­tibulitis had positive PST; causes for positive PST  —  IC; radiation cystitis; benign prostatic hyperplasia (BPH); 16%-20% of patients with lower urinary tract symptoms (LUTS); prostatitis (84%); overactive bladder (71%); acute bacterial cystitis; pelvic pain urgency/frequency questionnaire  —  1 page; validated in 335 patients and 51 con­trols; higher scores associated with higher likelihood of positive PST; 1 in 4 women show chronic active symptom­atology (consistent with PST results)

Overactive bladder: urodynamics comparing infusions of potassium and sodium  —  in patients with IC or overactive bladder, potassium caused 40% greater reductions in bladder volume; classification  —  speaker considers overactive bladder “euphemism for urgency and frequency”; significant high-quality data suggest overactive bladder should not be distinguished from IC

Successful Current Therapies for Interstitial Cystitis

Treatments: severity of disease determines treatment; correcting epithelial dysfunction  —  level I data show efficacy of heparinoids; patients showing no improvement require more therapy; reducing nervous activity  —  also interferes with protective function of bladder nerves; does not treat disease process; necessary for allowing patient immediate relief; allergy control  —  critical; two-thirds of otherwise stable patients with IC show exacerbations associated with seasonal allergies

Pentosan polysulfate: in speaker’s experience, sufficient treatment improves IC in 90% to 95% of patients; random­ized prospective study of 3 dosages of pentosan polysulfate  — 3 sites and 400 patients; all dosages showed steady improvements in 4 to 32 wk (70% efficacy at 8 mo); speaker typically gives 200 mg bid (double in men and women showing no response after 4 mo)

Hydroxyzine (eg, Atarax): significant effect on mast cells (stabilizes production and release of histamine; effects in­crease after 1 mo); available in generic form; speaker starts with 10 mg and increases to 25 mg as necessary; con­tinuous therapy recommended (patients often discontinue when symptoms subside); warn patients about sedation (significantly affects compliance; begin dosing in evening); randomized double-blind study  —  4 arms (placebo, pentosan polysulfate, pentosan polysulfate plus hydroxyzine, and hydroxyzine alone); only pentosan polysulfate and pentosan polysulfate plus hydroxyzine showed efficacy

Lidocaine: heparin  —  effect builds gradually over time and improves with more frequent treatment; traditionally, new patients with severe pain did not receive immediate relief; alkalinized lidocaine  —  deionization allows lido­caine to pass through lipid membranes; standard lidocaine or bupivacaine plus epinephrine (eg, Marcaine) not ab­sorbed by bladder (alkalinization increases absorption of lidocaine to »20%); effective at restoring bladder function when combined with heparinoids; ensure empty bladder before treatment (significant diuresis during procedure acidifies solution and prevents absorption); study of lidocaine concentration  —  stepwise increase from 80 mg to 160 mg showed significant improvement; 80% of patients showed remission after 6 treatments over 2 wk (indicates usefulness as diagnostic tool); response  —  typically lasts 2 to 4 hr (10%-20% of patients report effects lasting 1 day); response study  —  double-blind randomized controlled trial in 4 centers; 19 subjects received drug or placebo in random order; lidocaine solution showed 51% positive response (vs 10% with placebo; best trial results ever re­corded with IC)

Conclusion: speaker does not recommend narcotics due to upregulating effect on pain fibers; data suggest anticholin­ergics and antimuscarinics have beneficial effects on sensory nerves (tricyclic antidepressants show similar effi­cacy, but may be poorly tolerated due to side effects)

Questions And Answers

Speaker’s treatment: turbidity  —  bicarbonate precipitates lidocaine (heparin keeps lidocaine in solution); turbidity dependent on type of heparin solution used (speaker recommends turbid solutions, ie, emulsified state); oral pento­san polysulfate  —  given when bladder instillations begin; prevents symptoms and exacerbations between instilla­tions; overactive bladder  —  patients should show response after 2 to 3 wk (patients with severe urgency often show immediate response); 3 treatments per week ideal (patients with severe IC may require treatment daily or several times daily; 4 to 5 times per day safe); tricyclic antidepresssants  —  in speaker’s experience, superior to anticholin­ergics (without factoring in side effects); cystectomy  —  role in treatment of IC decreased significantly in past 10 yr; pouchitis  —  occurs in >24% of patients with IC; patients undergoing cystectomy require heparin (in pouch) or ileal conduit urinary diversion to protect neobladders from toxic factors in urine

Suggested Reading

Argade SP et al: Abnormal glycosylation of Tamm-Horsfall protein in interstitial cystitis patients. BJU Int. 103:1089, 2008; Nickel JC et al: Improvement of sexual functioning in patients with interstitial cystitis/painful bladder syndrome. J Sex Med 5:394, 2008; Nickel JC et al: Randomized, double-blind, dose-ranging study of pentosan polysulfate sodium for interstitial cystitis. Urology 65:654, 2005; Parsons CL et al: Defective Tamm-Horsfall protein in patients with interstitial cystitis. J Urol 178:2665, 2007; Parsons CL: Advances in the treatment of interstitial cystitis. Expert Opin Pharmacother 7:411, 2006; Par­sons CL: Argument for the use of the potassium sensitivity test in the diagnosis of interstitial cystitis. Int Urogynecol J Pelvic Floor Dysfunct 16:430, 2004; Parsons CL: Successful downregulation of bladder sensory nerves with combination of heparin and alkalinized lidocaine in patients with interstitial cystitis. Urology 65:45, 2005; Parsons CL: The role of the urinary epithe­lium in the pathogenesis of interstitial cystitis/prostatitis/urethritis. Urology 69:9, 2007; Rajasekaran M et al: Toxic factors in human urine that injury urothelium. Int J Urol 13:409, 2006; Rosenberg M et al: Interstitial cystitis: a primary care perspec­tive. Cleve Clin J Med 72:698, 2005; Stanford EJ et al: The emerging presence of interstitial cystitis in gynecologic patients with chronic pelvic pain. Urology 69:53, 2007; Stein P et al: Tamm-Horsfall protein protects urothelial permeability barrier. Urology 66:903, 2006; Teichman JM, Parsons CL: Contemporary clinical presentation of interstitial cystitis. Urology 69:41, 2007.