Gisela Chelimsky, MD Professor of Pediatrics

Medical College of Wisconsin USA

!! Spouse advisory board for Lundbeck and Ironwood (2014) Pharmaceutical

!! Many medications discussed are used “off label”

!! Appreciate the epidemiologic importance of comorbidities associated with chronic pelvic pain (CPP)

!! Understand the frequent comorbid conditions associated with CPP

!! Know the current understanding of order of development of comorbid conditions

!! Recognize differences in comorbid conditions in IC/BPS and MPP

!! Very prevalent !! They increase drastically the cost of medical

care !! They increase the number of procedures and

evaluations performed !! Often part of chronic overlapping pain

conditions

!! Conditions characterized by symptoms such as chronic pain, fatigue, sleep disturbances, and often disability

!! Other synonyms: "! Functional somatic syndromes "! Medically unexplained symptoms "! Somatoform disorders

!! The term chronic overlapping pain conditions implies that comorbidities are intrinsic

!! Until recently we have conceptualized these disorders as though they primarily involved the end organ

!! Each practitioners obtains a different history based on their specialty – practice medicine in silos

Rodriguez, M J Urol. 2009

!! Functional disorder n. A physical disorder in which the symptoms have no known or detectable organic basis but are believed to be the result of psychological factors such as emotional conflicts or stress. Also called functional disease

!! A functional disorder is a medical condition that impairs the normal function of a bodily process, but where every part of the body looks completely normal under examination, dissection or even under a microscope.

The American Heritage® Stedman's Medical Dictionary (dictionary.com)

Wikipedia

!! Strictly the second meaning, implying a change in function has impacted one or many end organ affected

!! Best example of differentiating a functional disease vs structural comes from GI disorder: irritable bowel syndrome (IBS), as opposed to structural GI disorders such as inflammatory bowel disease (IBD)

!!Think: hardware vs software

!! Most of the studies regarding comorbidities of pelvic pain were published after 2005

!! 2009: association between urologic conditions and IBS

Rodriguez, J Urol 2009

IBS CFS FM MHA Panic attacks

Depression

Clemens 2006

40% 16% 32%

Warren 2009

28% 9% 4% 36% 27% 42%

Nickel 2010

39% 18% 10% 30%

Clemens 2012

40% 22% 15% 25% 27% 55%

Our data 2016

50% 19% 22% 38% 3% 9%

Clemens Urology 2012

!! IC /BPS = 16185 ; non-IC/BPS = 32,370 !! No difference in age and gender; mean age of 46

years; 73.3 % women !! Average follow-up BPS/IC group (4.7 years); non-IC/

BPS group (5.4 years) !! No ICD codes for depression, anxiety or insomnia

before the index dx entry date !! IC/BPS had a significant higher incidence rate of

developing anxiety, depression, and insomnia than the matched controls (92.9 vs 38.4, 101.0 vs 42.2, 47.5 vs 23.0; per 10,000 person-year)

Chuang, Y Int Urol Nephrol 2015

!! Anxiety disorder: panic disorder, agoraphobia, specific phobia, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, and generalized anxiety disorder

!! 2,376 subjects (396 IC/BPS and 1,980 controls) 5.7 % had received an Anxiety Disorder (AD) diagnosis before the index date

!! IC/BPS group: 16.2% had an AD vs 3.6% controls (p < 0.001)

!! After adjusting for CPP, IBS, fibromyalgia, migraines, sicca syndrome, allergies, asthma, and OAB, the OR for prior AD among IC/BPS was 4.37 (95% CI = 2.16–8.85, P < 0.001) compared to the controls

!! 291 women aged 18-45!years with dx of IC/BPS and 873 randomly selected controls matched on age and index date of ambulatory care visit

!! IC/BPS: 29.9% had previous hx of dysmenorrhea vs 18.7% of controls

(adjusted odds ratio 1.59 (95% confidence interval 1.13-2.23, p!=!0.007) after adjusting for medical co-morbidities)

Chung, SD Acta Obstet Gynecol Scand. 2014

0

10

20

30

40

50

60

Percent of Each Comorbidity in IC/BPS +/- MPP

Percent

Our data: about 50% of IC/BPS have comorbid MPP

!! NIH-NIDDK MAPP group describes 2 phenotypes: "! Pelvic pain only (PP only) "! Pelvic pain and beyond (PP and beyond)

!! Two different disorders? "! PP beyond may be part of the chronic overlapping

pain conditions "! About 2/3 of women with IC/BPS have at least 1

comorbid diagnosis (Clemens Urology 2012)

Differences in pain distribution between IC/BPS subjects with PP only and PP beyond

Nickel JC, Tripp DA and the International Interstitial Cystitis Study Group. J Urol 2015

PP beyond: •! worse physical quality of

life •! greater sleep disturbance •! higher prevalence of IBS

and fibromyalgia •! more fatigue •! more psychiatric

conditions

PP only: •! worse sexual pain score

!! 164 consecutive patients at 6 month FU (mean 52 years, 69% female, median IBS duration 17 years)

!! Though 88% consulted GP, only 19% for IBS Sx !! Mean sick days:

"! For IBS: 1.7 "! For Comorbidities: 16.3 (p < 0.01)

!! Costs: "! IBS: 954 NOK "! Comorbid symptoms: 14854 NOK (p < 0.001)

!! Age, non-IBS diseases and somatic symptoms, not IBS severity: significant predictors for total costs

Johansson et al. BMC Gastroenterology 2010,10:31

Clemens UROLOGY 2012

Migraine (24 yrs) Depression (29 yrs) Panic attacks (31 yrs)

Fibromyalgia (38 yrs) Chronic fatigue syndrome (35 yrs)

IC/BPS (32 yrs) IBS (32 yrs)

Early

Late

Dysmenorrhea 84% IC/BPS

80%

IBS 75%

Fibromyalgia 69%

MPP 67% CFS 67%

CRPS 31%

Abdominal migraine 16%

CVS 9%

Migraine 85%

EARLY

LATE

Migraine 85%

MPP

CRPS 31%

migraine 16%

CVS 9%

Order of development of comorbidities when considering that if a disorder is not present at study enrollment, it may develop later

Adjustment disorder 84%

Syncope 76%

Migraine 74%

Dysmenorrhea 69%

IC/BPS 47% (NS)

Abdominal migraine

8%

PTSD 87%

EARLY

LATE

PTSD 87%

Syncope 76%

IC/BPS 47% (NS)

migraine

Anxiety 74%

MPP 36% (NS)

Anxiety 74%

Order of development of comorbidities when both comorbidities are present at study enrollment

Migraine Depression

Panic attacks

Fibromyalgia Chronic fatigue syndrome

IC/BPS IBS

Early

Late

Dysmenorrhea

IC/BPS

Abdominal migraine

Dysmenorrhea

migraine

Anxiety

MPP

PTSD Depression

Migraine

Syncope

IC/BPS

MPP

Clemens UROLOGY 2012

Anxiety Migraine

Our data

Are the comorbidities in IC/BPS similar as in MPP?

!! MPP: at least 3 months of non-cyclic CPP unrelated to bladder filling or emptying, AND a minimum NRS 4/10 using 2kg pressure in at least 2 of 5 examined pelvic floor TPs (levator ani, obturator internus, and midline perineum (Sanses, T 2015)

!! IC/BPS: at least 6 months of urgency, frequency, and bladder pain clearly linked to bladder filling and emptying

Tender-points in healthy controls, IC/BPS, MPP and IC/BPS with MPP

Sanses, T Clin J Pain 2016

P=0.05

0% 10% 20% 30% 40% 50% 60% 70%

Panic Reflex Syncope

Raynauds Dyspepsia

CIN CFS FM

Dysmenorrhea RA

POTS MCS TMJ

MHA Endometriosis

Asthma Adjustment Disorder

Autonomic Neuropathy CRPS

Syncopal Migraine Diabetes

IBS Generalized Anxiety

Dyspareunia SFIBS

CVS FAP

PTSD Abdominal migraine

IC

MPP

p<0.01 P=0.06

P=0.08

IC/BPS and MPP share most of the same comorbidities, except that MPP has higher prevalence of dysmenorrhea and PTSD

P=0.02 P=0.06

P=0.06

0% 10% 20% 30% 40% 50% 60% 70%

Panic

Reflex Syncope

Raynauds

Dyspepsia

CIN

CFS

FM

Dysmenorrhea

RA

POTS

MCS

TMJ

MHA

Endometriosis

Asthma

Adjustment Disorder

Autonomic Neuropathy

CRPS

Syncopal Migraine

Diabetes

IBS

Generalized Anxiety

Dyspareunia

SFIBS

CVS

FAP

PTSD

Abdominal migraine

Both dx

One dx

P=0.04

P=0.05

Having IC/BPS and MPP increases the prevalence of having dysmenorrhea, CFS, panic attacks and also FM and dyspepsia (p=0.06)

!! Two phenotypes of CPP: PP beyond, PP only !! Comorbidities are very common in IC/BPS PP

beyond, mainly IBS, chronic fatigue, fibromyalgia and depression

!! Migraine, depression, anxiety, PTSD and dysmenorrhea usually present before the onset of IC/BPS

!! Having IC/BPS and MPP increases the risk of other comorbidities

ICEPAC STUDY SUPPORTED BY NIDDK (R01DK083538) COLLABORATORS

!!ICEPAC Study Advisory Board: "! Debra Erickson, M.D. University of

Kentucky College of Medicine, Lexington, KY, USA

"! Kathleen Pajer, M.D., M.P.H. Children’s Hospital of Eastern Ontario, Ottawa, ON

"! Julian Thayer, Ph.D. The Ohio State University, Columbus, OH, USA

"! Ursula Wesselmann, M.D., Ph.D. UAB School of Medicine, Birmingham, AL, USA

"! Denniz Zolnoun, M.D., M.P.H. UNC School of Medicine, Chapel Hill, NC, USA

"! C.A.Tony Buffington, DVM, PhD, The Ohio State University, Columbus, OH, USA

!! Jeff Janata, PhD !! Tatiana Sanses, MD !! Adonis Hijaz, MD !! Sangeeta Mahajan, MD !! Robert Elston, PhD !! Elais Veizi, MD !! Brad Fenton, MD PhD !! Ajay Singla, MD

Supported by an Advancing Healthier Wisconsin grant 5520298