1. PROMIS: THE GOOD, THE BAD & THE UNAPPEALING: ABDOMINAL SYMPTOMS MARGARET HEITKEMPER UNIVERSITY OF WASHINGTON

2. Irritable Bowel Syndrome Chronic abdominal pain associated with bowel pattern changes (Rome III criteria) Constipation Diarrhea Mixed 10-17% of US population Most frequently diagnosed in women Heterogeneous – range from mild to severe

3. PROMIS OVERVIEW 2 IBS STUDIES All incorporated PROMIS measures to look at biological outcomes – Jarrett – Cain

4. Irritable Bowel Syndrome Questions: Are there biomarkers for symptoms in a functional disorder such as IBS? What do the PROMIS© measures tell us?

5. Irritable Bowel Syndrome ANSWER: It depends

6. PATHWAYS TO ABDOMINAL PAIN N = 20 IBS; N = 20 controls Physiological measures – Central pain processing – Proteomic/genetic – Inflammatory markers – Videocapsule

7. PATHWAYS TO ABDOMINAL PAIN Purpose Compare conditioned pain modulation (CPM) in women with IBS to healthy control (HC) women. Test relationships of CPM ‘efficiency’ with IBS and psychological symptoms in women with IBS to HC women.

8. If a patient be subject to two pains arising in different parts of the body simultaneously, the stronger blunts the other. Hippocrates’ aphorism (460 – 377 BCE) 8 Diffuse Noxious Inhibitory Control (DNIC) System Conditioned Pain Modulation (CPM) Irritable Bowel Syndrome

9. Experimental Model CPM Mimic naturally occurring pain inhibiting processes. How much does the conditioning (noxious) stimulus reduce the pain response evoked by the other noxious stimulus, the test stimulus? Test stimulus Conditioning stimulus

10. Cortex Thalamus Spinal cord Caudal Medulla Peripheral sensory nerve 10 pain signals 2 1 IBS patients – CPM inefficiency in 3 studies of women

11. PATHWAYS TO ABDOMINAL PAIN 20 IBS; 20 age-matched control women Pain was rated on verbal numeric pain scale.

12. Methods Recruited – local community Screening – eligibility  Women 18 - 45 years  IBS: Diagnosis by HCP, current symptoms, no other pain disorders  Control group – healthy with no pain disorders Visit-1: Written consent, review questionnaires, brief history & physical (NP) Visit-2: CPM testing in AM during follicular phase (menstrual cycle), 2-week diary of GI and psychological symptoms, stools, medication use 12

13. PATHWAYS TO ABDOMINAL PAIN 14-DAY DIARY (39 items) – 0 = NOT PRESENT – 1 = MILD – 2 = MODERATE – 3 = SEVERE BOWEL DISEASE QUESTIONNAIRE SCL – 90 IBS – QUALITY OF LIFE (QOL)

14. PROMIS MEASURES Pain interference Pain behavior Pathways to Abdominal Pain Supported by NINR, NIH

15. PATHWAYS TO ABDOMINAL PAIN Pain Behavior Short Form (PROMIS®) – Common pain behaviors (sighing, crying,), pain severity behaviors (resting, guarding, facial expressions, asking for help) and verbal reports of pain. Pain Interference - Short Form (PROMIS®) – The extent to which pain hinders engagement with social, cognitive, emotional, physical and recreational activities as well as sleep  Past 7 days

16. CPM Technique Medoc's PATHWAY Pain & Sensory Evaluation System (Israel) Temperatures 0ºC to 55ºC Heating and cooling rate up to 8ºC/second Thermode 30 X30 mm Study maximum thermode temperature 48ºC (118.4 ºF) 16

17. Orientation & familiarization  Dominant hand  43ºC & 44ºC for 7 sec  Rate pain at 6 sec  Return 32ºC (90ºF) (baseline ) Rest 5 min Pain-6 determination  45ºC, 46ºC, 47ºC, 48ºC  Confirm temp at the pain rating of 6 Test stimulus Conditioning stimulus 17 CPM Protocol

18. 18 Orientation Familiarization Rest 5 min break Pain-6 temperature determination Rest 5 min break Test stimulus  Thermode set to pain- 6 temperature  Rate pain at 0, 10, 20, 30 sec Rest 5 min Conditioning stimulus CPM Technique

19. Pain rating of test stimulus during conditioning stimulus  Hand in 12ºC water bath for 60 sec.  At 10, 20, 30 sec - rate how painful sensation is with a hand in the water bath  Thermode is set to Pain-6 level  At 40, 50, 60 sec rate how painful the sensation is CPM Efficiency Pain ratings non-conditioned (test) minus pain ratings conditioned 19

20. Sample Characteristics HC (n = 20 IBS (n = 20 P-value Demographics Age27.6 (5.5)27.4 (6.6).940 Race, % White75% 1.00 College Degree90%65%.127 Daily symptoms, % days moderate/severe symptoms over 2 wks Abdominal Pain4.0 (9.8)28.0 (22.4)<.001 IBS symptoms4.9 (11.4)59.0 (24.2)<.001 Anxiety1.2 (2.9)17.0 (20.2).001 Depressed0.4 (1.9)7.5 (13.9).029 Stressed6.5 (17.2)19.3 (20.2).008 20

21. Irritable Bowel Syndrome PROMIS PAIN© N=20 BEHAVIOR 54.1 (8.2) INTERFERENCE 56.8 (7.7) Daily Diary (14days) ABDOMINAL PAIN.428*.416* ABD PAIN POST EATING.340.451* ABD DISTENTION.205.285 RETROSPECTIVE (3m) ABDOMINAL PAIN.425*.430* WHEN YOU HAD IT – DID IT RESTRICT YOUR ACTIVITIES.318.307 QUALITY OF LIFE PHYSICAL FX-.502*-.601* EMOTIONAL FX-.471*-.300 * P <.1

22. Pain ratings relative to thermode temperature 22 Note. HC = Healthy Controls. IBS = Irritable Bowel syndrome. Linear regression used to extrapolate high temperatures for some people. Thermode temperature N HC (n = 20) N IBS (n = 20) P- value 45 20 2.16 (1.48) 20 2.85 (2.22).255 46 20 2.92 (1.75) 20 4.10 (2.13).063 47 20 4.15 (1.74) 20 5.68 (2.05).015 48 20 5.54 (2.14) 20 7.11 (2.32).033

23. CPM efficiency 23 P <.001

24. Scatterplot of CPM with IBS and Psychological Symptoms with Outlier 24

25. Correlation of CPM Efficiency with Pain Interference and Pain Behavior Pain Behavior (-.31,.17; -.38,.111) Pain Interference (-.30, -.27, NS)

26. PATHWAYS TO ABDOMINAL PAIN 2 nd Study Comprehensive Self Management N=86 women with IBS Baseline Biological Measures – Genetics – Proteomics – Heart rate variability – Intestinal permeability

27. 27 IBS interference Intensity vs ‘Physiological Group’ in IBS Subjects (n=86) INTENSITY – IBS Interference LOW -- (HRV) -- HIGH

28. Abdominal Pain in Women with IBS, PMS & Dysmenorrhea IBS Women with PMS & dysmenorrhea report greater menses-linked amplification of abdominal pain symptoms Days pre-menses / Days post onset 32 1 -2 -3 -4 -5-6-6-7-7-8-8-9-10 Mean Abdominal Pain 3.0 2.5 2.0 1.5 1.0.5 0.0 IBS+Dys+PMS IBS+PMS IBS+Dys IBS only Control

29. Conclusions PROMIS MEASURES – GOOD Compare to national populations (age, gender) Compare to other patient populations Add to data base with similar tools for symptoms PROMIS PROFILE (29 items) – BAD One more tool – UNAPPEALING Use of screening? Vetted by FDA for treatment trial outcomes? Limited access

30. Thank you