CHRONIC PELVIC PAIN: OVERLAPPING DISEASES
Educational Objectives
| The goal of this program is to increase the clinician’s awareness and improve the management of diseases that can exist
concurrently with chronic pelvic pain. After hearing and assimilating this program, the clinician will be better able
to:
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 | 1. Implement a symptom-based approach to diagnosing irritable bowel syndrome (IBS).
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| 2. Discuss recent insights into the pathogenesis of IBS.
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| 3. Counsel patients about the role of food as well as pharmacologic therapies in controlling symptoms of IBS.
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| 4. Identify patients with chronic pelvic pain who may have interstitial cystitis (IC).
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| 5. Discuss the pathophysiology thought to be involved in IC.
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Acknowledgments
Dr. Chey was recorded at the 12th Annual Common Problems in Office Practice, sponsored by the University of Michigan
Medical School, and held on March 15, 2008, in Plymouth, MI. Dr. Cervigni was recorded at Advances in Urogynecology
and Reconstructive Pelvic Surgery, sponsored by Northwestern University’s Feinberg School of Medicine and
The Evanston Continence Center, and held on June 7-9, 2007, in Chicago, IL.
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. Chey acts as a consultant to and is on the Speaker’s Bureaus of Axcan Pharma Inc, Procter & Gamble,
Salix Pharmaceuticals, and Takeda Pharmaceutical Company. Dr. Chey also acts as a consultant to AGI Therapeutics
and Novartis. Dr. Cervigni and the planning committee reported nothing to disclose.
| IRRITABLE BOWEL SYNDROME —William D. Chey, MD, Professor, Department of Internal Medicine; Director,
Gastrointestinal Physiology Laboratory, and Director, Office of Clinical Research, Division of Gastroenterology, University
of Michigan Medical School, Ann Arbor
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| Introduction: prevalence—≈1 in 7 people in general population have symptoms that qualify them for diagnosis of
irritable bowel syndrome (IBS); Rome III diagnostic criteria—developed by consensus group of international experts
in functional bowel disease; clinical features—recurrent abdominal pain or discomfort (duration ≥3 mo); alterations
in bowel functions, with ≥2 of following characteristics, 1) symptoms improve with defecation; 2) onset
associated with change in frequency of stool, or 3) onset associated with change in appearance of stool; in addition,
there should be no evidence of organic disease that might explain symptoms; treatment based on IBS subtypes, ie,
IBS with constipation (IBS-C), IBS with diarrhea (IBS-D), IBS with mixed stools (IBS-M); Rome III guidelines
rely more on stool consistency than stool frequency
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| Diagnostic algorithm: symptom-based criteria; persistent or recurrent abdominal pain or discomfort associated
with change in bowel function; exclude alarm symptoms (eg, weight loss, fever, unexplained bleeding, family history
of cancer, inflammatory bowel disease); ask about family history of celiac disease (20% risk for celiac disease
with firstdegree relative with celiac disease); perform physical examination and selected diagnostic tests to rule out
organic disease; make confident diagnosis of IBS; initiate treatment plan based on predominant symptoms; monitor
patients regularly until confident diagnosis correct and treatment effective; more on diagnosis—diagnosis of exclusion;
broad differential diagnosis; 90% chance of correct diagnosis if standardized criteria employed and alarm
symptoms excluded; evolving data on role of celiac sprue in IBS and small bowel bacterial overgrowth (IBS evolving
towards infectious disease); pretest probability of organic disease—inflammatory bowel disease, colon cancer,
thyroid dysfunction, lactose malabsorption; data show evidence of organic disease no more likely in patients with
IBS than in general population
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| Screening for celiac disease in patients with suspected IBS: interim analysis from ongoing large prospective
trial (500 patients each arm) shows prevalence of celiac antibodies significantly higher in IBS patients than in general
population; however, prevalence of biopsy-proven celiac disease in patients with IBS ≈2-fold higher but not statistically
greater than in general population; data supported by meta-analysis; American College of Gastroenterology
guidelines—recommend screening for celiac disease in patients with IBS-D or IBS-M; anti-tissue transglutaminase
(tTG) and anti-endomysial (EMA) antibodies highly specific (>95%); sensitivity >90% in patients with complete
villous atrophy; sensitivity lower (≈70%) in patients with partial villous atrophy or intraepithelial lymphocytosis, ie,
Marsh type 1 lesion (most patients with celiac disease in United States); screen for tTG and EMA; in patient with
high pretest probability of celiac disease (eg, family history, diabetes), permissible to perform endoscopy and small
bowel biopsy without serology, or even if serology negative
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| Small intestinal bacterial overgrowth in IBS: data suggest small intestinal bacterial overgrowth may occur
more commonly in patients with IBS than in controls; Swedish data show no statistically significant difference in
likelihood of positive lactulose or glucose breath testing and no difference in small-bowel bacteria (using standard
definition of >105 organisms per colony-forming unit) in patients with IBS, compared to controls; however, dramatic
difference in likelihood of abnormality and IBS, compared to controls, when threshold lowered; stool studies
suggest different types of bacteria in bowel of patients with IBS, compared to controls
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| Therapy: tierd approach to treatment; choice of medication determined by frequency and severity of symptoms, as
well as specific symptoms; important to reassure patient that diagnosis correct and to explain cause of symptoms
and treatment approach; pharmacologic therapy and routine monitoring necessary for patient with moderate symptoms;
refer patient with severe symptoms to gastroenterologist; psychologic comorbidities (eg, depression, anxiety)
must be addressed to improve gastrointestinal (GI) symptoms
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| Food: likely plays significant role in symptoms; two-thirds of patients diagnosed with IBS associate symptoms with
eating; increased colonic contractions after eating meal normal (gastrocolonic response); person who does not have
IBS unaware of contractions; in IBS, contractions heightened in magnitude and/or frequency, and patients feel them
more; fermentation and gas handling abnormal; psychologic feedback loop can develop around eating (autonomic nervous
system stimulated); patient may not want to leave house because of symptoms; integrated response; patients may
develop food intolerances, ie, develop GI symptoms in response to eating certain foods; dietary advice—no standardized
functional GI diet; avoid foods that stimulate GI tract, eg, patients with IBS-D should avoid caffeine, chocolate,
alcohol, and poorly absorbed carbohydrates (particularly in individuals with gas or bloating); carbohydrates main
driver for gas formation within GI tract; artificial sweeteners are sugar alcohols that ferment in GI tract, resulting in
gas; use food diary to identify trigger foods; dietary fiber recommended for patients with constipation-related symptoms;
exclusion diets—preliminary data show effective in some patients; however, adherence to true exclusion diet
difficult
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| Pharmacologic therapies: choose based on predominant symptoms (eg, pain, diarrhea, constipation, bloating);
limited effectiveness; unrealistic to expect >30% to 50% response rate with any IBS medication
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| Antispasmodics: most commonly prescribed for IBS in United States; octylonium bromide not available in United
States; little evidence supporting or not supporting use of hyoscyamine or dicyclomine (side effects dry mouth,
constipation, urinary retention, and visual disturbances); increased likelihood of side effects (many cardiovascular)
in elderly patients
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| Antidepressants: rationale for antidepressant therapy—evidence for visceral hypersensitivity, increased psychosocial
distress, and history of physical abuse in IBS patients; evidence that antidepressants improve somatic and visceral
pain; antidepressants also have effect on GI transit; desipramine vs placebo—data show no statistically significant
benefit of desipramine [tricyclic antidepressant (TCA)], compared to placebo at end of 12 wk; subgroup
analysis of compliant patients shows highly statistically significant benefit in patients on desipramine, compared
to placebo (>25% of patients in study lost because of side effects); estimated up to one-third of patients cannot
tolerate TCAs; when tolerated, TCAs effective in relieving pain and symptoms; benefits may not be dose-dependent;
lower doses often beneficial in IBS; warn patients about side effects; clinical benefits for pain and GI symptoms
may be seen before antidepressant effects; little benefit in relieving anxiety; selective serotonin reuptake
inhibitors (SSRIs) more effective for treating anxiety
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| Serotonergic agents: tegaserod—withdrawn from US market because of imbalance in incidence of cardiovascular
events among subjects in clinical trials program (not in clinical practice); alosetron—5HT receptor antagonist;
shown beneficial in short- and long-term studies for patients with IBS-D; higher likelihood of ischemic colitis and
severe constipation; medication restricted to women with severe IBS-D who fail to respond to conventional therapy;
completion of educational module required before prescribing; lubiprostone—chloride channel activator; targeted
for patients with chronic constipation; shown more effective than placebo in improving global and individual
symptoms in patients with IBS-C
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| Questions: peppermint oil—smooth muscle relaxant (calcium channel blocker); studies suggest benefit in patients
with IBS or painful spastic conditions of GI tract; use associated with high likelihood of inducing reflux symptoms;
30% to 40% of IBS patients have reflux; Bifidobacter infantis—only probiotic rigorously tested in IBS; shown more
effective than placebo (2 trials) in improving IBS symptoms (one showed correction in systemic cytokine abnormalities
in patients with IBS after taking B infantis for 12 wk); useful for symptoms of bloating; consider adding to
therapy; successful treatment of celiac disease—leads to normalization of antibody testing; clinical experience that
most patients with IBS who also have celiac disease and go on gluten-free diet experience relief of IBS symptoms
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| INTERSTITIAL CYSTITIS (IC) —Mauro Cervigni, MD, Professor of Urogynecology, Catholic University, and
Chair, Urogynecology Unit, San Carlo di Nancy Hospital, Rome, Italy
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| Sources of chronic pelvic pain (CPP): bladder source of CPP in >30% of female patients; endometriosis, GI
disorders, recurrent urinary tract infection (UTI), pelvic infection, vulvodynia, and IC overlapping diseases
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| Definition of IC: urinary urgency, frequency, and or pelvic pain in absence of bacterial infection; few specific diagnostic
criteria and no agreed-on pathophysiology, evaluation, or treatment make condition difficult to describe; IC
disease with specific symptoms related to bladder (eg, frequency, urgency, nocturia, bladder pain); diagnosis dependent
on physician awareness and suspicion, despite intensive amount of research
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| Epidemiology; prevalence—varies significantly from 18.1 per 100,000 women in Finland to 1.2 per 100,000
women in Japan; 60 per 100,000 women in United States; 995 per 100,000 women in United States among first-degree
relatives of women with IC; spectrum of disease—from misdiagnosed recurrent UTI to advanced IC; typically
diagnosed late in disease continuum; patient sees ≥5 physicians before diagnosis; risk for unnecessary hysterectomy;
decreased quality of life; 2 to 7 yr between development of symptoms and diagnosis; no correlation between
bladder cancer and IC; frequency of IC lower in patients with diabetes than in nondiabetics; causes—infection, autoimmune
disorders, dysfunctional bladder epithelium, mastocytosis, neurogenic inflammation, toxic substances in
urine, psychosomatic causes, and food intolerance; proposed theories—disruption of glycosaminoglycan (GAG)
layer; neurogenic inflammation
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| Neurogenic inflammation: stimulation of peripheral nerves elicits vasodilation, plasma extravasation, and other
inflammatory changes; can be evoked in bladder (and other target organs) by antidromic stimulation of visceral afferents
in pelvic nerve; similarities in clinical features and disease course between IC and neurovascular disorders,
eg, reflex sympathetic dystrophy; continuous cycle of bladder insult, epithelial layer damage, potassium leakage
into interstitium, activation of C fibers and release of substance P, mast cell activation, histamine release and more
injury; key factor potassium that migrates into mast cells through defect in membrane and stimulates inflammatory
substances that cause symptoms; urothelial dysfunction—mast cell activation and C-fiber up-regulation leads to
windup phenomenon in spinal cord and central nervous system; this creates visceral organ hyperalgesia or allodynia;
viscero-visceral hyperalgesia—“cross-talk” (referral of pain from skin to viscera and vice versa; chronic pain
syndrome with multiple organ symptoms (eg, IBS, endometriosis, vulvodynia, IC)
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| Urinary markers hypothesis: IC begins with epithelial abnormalities, resulting in stimulation of afferent nerves,
edema, and sometimes inflammatory infiltrate; aberrant nerve activity results in epithelial abnormalities and inflammatory
infiltrates; bladder epithelial growth factor EGF—produced mainly in thick ascending loop of Henle and distal
convoluted tubule, not in bladder; stimulates, but not required for bladder epithelial cell proliferation in vitro;
heparin-binding epidermal growth factor-like growth factor (HB-EGF)—produced by kidney and bladder epithelial
cells; required for bladder epithelial cell proliferation in vitro; antiproliferative factor (APF)—causes decreased rate
of cell proliferation, decreased production of HB-EGF production and increased production of other markers, and altered
gene expression of 15 other cell proteins; urinary markers important in understanding cause of IC; statistical
difference between patients with IC and controls
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| Evaluation: urinalysis, voiding diary, questionnaire (pain, urgency, frequency), O’Leary-Sant IC symptom and
problem index questionnaire specific for evaluating patient suspected of having IC; urine culture; urine cytology;
pelvic examination (create pain map; patient with vulvodynia may have associated IC); cystoscopy with hydrodistention
(look for fissures and for Hunner’s ulcers, pathognomonic for IC); biopsy to determine possible presence of
mastocytosis, edema, or fibrosis of bladder; clear difference of opinion between Europe and United States about
need for cystoscopy with hydrodistention likely due to high cost of anesthesia in United States (done routinely in
Europe)
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| Associated conditions: >70% of patients with CPP diagnosed with IC and endometriosis (20% with IC alone and
10% with endometriosis alone); cystoscopy with hydrodistention to rule out IC recommended for woman scheduled
to undergo laparoscopy for CPP
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| Pharmacologic treatment: multimodal approach recommended; intravesical treatments—heparin, bacillus Calmette-Guerin
(BCG), dimethyl sulfoxide, hyaluronic acid, botulinum toxin type A (Botox); surgical treatment—
reserved for end-stage disease where there is low bladder capacity, severe pain, and associated urinary symptoms;
phantom pain possible after cystectomy; sacral neuromodulation—improvement in frequency and nocturia, increased
volume, and decreased pain; 94% success with staged procedure, compared to 52% with traditional percutaneous;
botulinum toxin— shown to increase functional bladder capacity, decrease bladder voiding pressure, and
inhibit afferent nerve-mediated bladder contraction; prolonged intravesical instillation of resiniferatoxin; posterior
tibial nerve stimulation—significant improvement of urgency, frequency, quality of life, and hypogastric nerve
pain; gene therapy—can lead to increased bladder expression of endorphins that can suppress nociceptive responses
induced by bladder irritation
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| Conclusion: multidisciplinary team recommended, consisting of urologist, urogynecologist, gynecologist, psychologist,
nutritionist, acupuncturist, pain clinic physician, and patient; Multinational Interstitial Cystitis Association
international organization dedicated to increasing awareness about IC and promoting communication among medical
professionals throughout world; IC not disease of bladder, but clinical syndrome characterized by urgency, frequency,
and pain due to development of neuropathology and resulting in visceral pain syndrome; visceral pain syndrome
involves chronic neurogenic inflammation, afferent overactivity, and central sensitization, which interact to
perpetuate pain; benefit of multimodal therapy realized when organ-based concept of IC abandoned and neuropathic
or visceral pain model accepted
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Suggested Reading
Cash BD, Chey WD: Irritable bowel syndrome — an evidence-based approach to diagnosis. Aliment Pharmacol
Ther 19:1235, 2004; Cash BD et al: The utility of diagnostic tests in irritable bowel syndrome patients: a systematic
review. Am J Gastroenterol 97:2812, 2002; Clemens JQ et al: Case-control study of medical comorbidities in
women with interstitial cystitis. J Urol, Apr 17 [Epub ahead of print]; Diggs C et al: Assessing urgency in interstitial
cystitis/painful bladder syndrome. Urology 69:210, 2007; Posserud I et al: Small intestinal bacterial overgrowth in
patients with irritable bowel syndrome. Gut 56:802, 2007.
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