Disclosure

1. Evaluating and Treating Pain in IBDEva Szigethy MD, PHD Associate Professor of Psychiatry, University of Pittsburgh Director, Medical Coping Clinic, Children’s Hospital of PittsburghDirector, Visceral Inflammation and Pain (VIP) CenterDivision of Gastroenterology, Hepatology, and NutritionDecember 12, 2013

2. Disclosure • Sources of Funding • CCFA Senior Investigator Award • NIMH R01 Grants • American Psychiatric Press Inc., Book Editor • Merck- Consultant, Advisory Board • All medication suggestions in this presentation are off-label uses unless noted otherwise.

3. Binion et al., 2010 Abdominal pain is common in IBD Of adults with IBD, 20% consume up to 80% of medical costs. Chronic pain and depression are key factors

4. Relationship between pain and telephone encounters in adults with IBD Ramos Rivers 2013

5. Multiple Factors to Consider for Causes of Pain in IBD • Inflammation • Anatomical- strictures/adhesions/fistulas • Bacterial overgrowth- small intestine • Neurobiological/Psychological • Psychosocial • Genetics Bielefeldt et al., Inflamm Bowel Dis 2009; Srinath et al., Ther Advances in Gastro 2012; Camilleri N Engl J Med 2012

6. IBD-IBS • 30-80% of adults with inactive IBD had irritable bowel syndrome (IBS) symptoms • Self-reported pain in 45%-100% pediatric patients with IBD • 10-40% with IBS • Over half depressed Simren et al., Am J Gastroent 2002 ; Minderhound et al., Dig Dis Sci 2004; Farrokhyar et al., Inflamm Bowel Dis 2006; Ansari et al., Eur J Gastro Hepatol 2008; Zimmerman et al., Inflamm Bowel Dis 2012, Crandall et al., J Ped Gastro & Nutr 2007 Greenley et al., J PedPsychol 2012

7. Unrecognized inflammation in adults with quiescent IBD Crohn’s Disease Ulcerative Colitis Keohane et al., Am J Gastroenterol 2010

8. Influences on Visceral Sensitization • Stress • Abnormal inputs • Repetitive bowel stimulation • Acute inflammation • Infection • IBD (mild or in remission) • Neurological trauma • Operations • Invasive procedures Zighelboim J, Dig Dis & Sci 1995; 40:819 Drossman DA et. al., Gastroenterology 2002

9. The brain can amplify the pain from the gut • Pain involves both the gut and brain • Acute GI pain usually results from injury to the gut (e.g., active disease or infection) • Chronic GI pain can result from the gut (visceral hypersensitivity), brain (central hypersensitivity), or both

10. ABDOMINAL PAINPsychological • Depression and anxiety in adult and pediatric IBD • Mood disorders linked to persistent pain in quiescent IBD • Increased worrying, limited coping ability, somatization • Mechanisms still unclear Szigethy et al. J Am Acad Child Adolesc Psychiatry. 2004; Fuller-Thomson, Sulman. IBD 2006; Farrokhyar et al. IBD 2006; Srinath et al. DDW 2011 (Abstract); Graff et al IBD 2009

11. ABDOMINAL PAINPsychosocial • Life stressors ~ coping  pain perception in IBD • Early life trauma linked to visceral hypersensitivity • Chronic stress reactivation risk Ross et al. JPGN 2011 Drossman. Am J Gastroenterol 2011 Engstrom J Am Academ Child Adolesc Psych 1991 Levenstein et al. Am J Gastroenterol 2000

12. Components of Pain History(Clinical Manual of Pain Management in Psychiatry, R. Leo, APPI 2007)

13. Pain is a modifiable experience Pain Experience • Cognitions • Hypervigilance • Attention • Catastrophizing • Neurobiological • Neurodegeneration • Maladaptive plasticity • Genetics • Mutations • Gene products Psychosocial Context • Pain beliefs • Cultural • Expectation • Conditioning • Social support • Stress • Sleep Injury • Peripheral and central sensitization • Mechanical Nociceptive Modulation

14. Pain Management

15. Education for Abdominal Pain • The goal of education is to communicate information to patients and families about abdominal pain and its connection with psychological triggers, as well as factors that may exacerbate pain, such as social reinforcement and school/work avoidance • Family therapy targets family interactions and relationships rather than the individual patient in order to change maladaptive behaviors, increase tolerance of symptoms and encourage independent coping skills. Brent M JPGN 2009; Bursch JPGN 2008; Walker Pain 2006; Chiou & Nurko, 2010

16. Education: Offering a Validated Explanatory Model for Pain

17. Cognitive Behavior Therapy (CBT) for Pain • CBT has most empirical support for treating depression and anxiety in adults with IBD • CBT alters behavior, perception, and thinking to change mood and sensations • CBT helps individuals to interrupt automatic emotional processing which maintains negative cognitions and rumination about pain • CBT teaches problem-solving skills based on personal control and the ability to adjust behavior and thoughts accordingly = stress management Palsson & Whitehead, 2013

18. Cognitive Behavioral Therapy versus medical treatment as usual for depressed adolescents with IBD • CBT modified to target illness perception and relaxation for pain Results • 3 month pre- post treatment: • Decreased depression • Improved quality of life • Improved abdominal pain Szigethy et al., 2004,2007,2009

19. Definition of Clinical Hypnosis • A state of inner absorption, concentration and focused attention • An altered state of consciousness with observable brain changes. • This “trance” allows access to primitive, automatic brain mechanisms to control perception, memory and somatic function. • Utilizes the human brain’s natural tendency to dissociate. Driving and missed your exit? …… Trance

20. Empirical Evidence for Hypnosis for IBS is growing • GI symptoms- pain, distention, motility • Rectal smooth muscle tone/sensitivity • Analgesic medicine use • Autonomic nervous system • Suffering- anxiety, depression, emotional awareness (CNS) • Quality of life • Functioning- work productivity, doctor visits Palsson & Whitehead, 2013

21. Hypnosis for IBD Adults • Improved IBD activity and circulating cytokines • Improved quality of life • Less corticosteroid use • Decreased rectal mucosal release of substance P, histamine • Decreased rectal blood flow • Maintaining remission in UC patients Children • Improved post-hypnosis in pain, diarrhea, inflammatory markers • Controlled for change in medical treatment Miller & Whorwell 2008, Mawdsley 2008 Shaol 2008; Keefer , 2013)

22. Common elements in empirically tested GI hypnosis • Brief and time-limited therapy (6-12 weekly or bi-weekly sessions) • Interventions are gut-focused: Gastrointestinal suggestions and gut imagery and metaphors targeting central symptoms of each disorder, and promoting normalization of gut functioning and reduced symptom experience. • Home practice used in between therapist visits with recorded hypnosis audio exercise or self-hypnosis

23. Examples of hypnotic language • “Your brain is now sending messages to the gut-control stations to tune down the intensity and quality of pain signals so that you feel less discomfort…” • “…your brain can easily and automatically filter out any uncomfortable sensations and allow in (warm, cool) comfortable sensations

24. Benefits of Psychological Treatment • High response rate (about 70%) • Can benefit patients not responding to medical treatments • Is additive to and possibly synergistic with medical treatments • No side effects • Benefits continue years after treatment ends • Reduces health care costs 2234

25. Pain Management: Medications • IBD Medications- remission is goal • Antispasmodics – beware of obstruction • NSAIDS and COX-2 inhibitors- beware of worsening IBD flare • Acetaminophen- no significant anti-inflammatory, gastric or renal effects but hepatotoxicity • Opioids- beware of long-term use • Psychotropics- do they work? Srinath et al.; 2012; Grover & Drossman IBD Monitor, 2009

26. Rationale for Antidepressants for IBD • Treatment of psychiatric co-morbidity • Peripheral effects • Motility / secretion • Afferent • Central pain modulatory effects 1252

27. Antidepressants: TCA, SSRI, SNRI • The neurochemicals targeted involved in visceral motility and sensation (IBS). • Unclear whether they directly impact nociception or their beneficial effects are mediated by decreasing anxiety and depression. • SSRI/SNRI: Few side effects or drug-drug interactions Mikocka-Walus BMC Gastroenterol 2007, 2009; Friedrich et. al. Clin. Ther. 2010 ; Rahimi 2009

28. Tricyclic Antidepressants (TCA) • Increase serotonin, endogenous opioid release, direct action on opioid receptors. Potentiate the actions of opiates requiring lower dose. • Effects on pain reduction and improved sleep more rapid than antidepressant effect (3-7 days) and at lower doses. • Anticholinergic side effects such as dry mouth, constipation, blurred vision, urinary retention, confusion, delirium. • Autonomic side effects include orthostatic hypotension, sweating, palpitations, tachycardia, increased blood pressure and prolonged QT, QRS and PR intervals and depressed ST segments requiring EKG monitoring.

29. Overall Forest Plot of Antidepressant Studies for IBS Tricyclic Antidepressants (TCAs) Treatment Control RR (random) Weight RR (random) n/N n/N 95% CI % 95% CI Heefner, 1978 10/22 12/22 5.94 0.83 (0.46, 1.51) Myren, 1982 5/30 10/31 2.66 0.52 (0.20, 1.33) Ngain, 1984 14/21 21/21 14.74 0.67 (0.49, 0.90) Boerner, 1988 16/42 19/41 7.63 0.82 (0.30, 1.36) Bergmann, 1981 5/19 14/16 3.82 0.30 (0.14, 0.65) Vil, 1991 14/25 20/2510.670.70 (0.47, 1.04) Drossman, 2003 60/115 36/37 16.77 0.83 (0.63, 1.08) Talley, 2008 0/18 5/16 0.33 0.08 (0.00, 1.36) Vahedi, 2008 8/27 16/27 5.02 0.50 (0.26, 0.97) Subtotal (95% CI) 319 256 67.36 0.68 (0.56, 0.83) 0.1 0.2 0.5 1 2 10 5 Favors treatment Favors control Total events: 32 treatments; 153 controls Test for heterogeneity: Chi2=10.94, df=8, (P=0.21), F=26.9% Test for overall effect: Z=3.86 (P=0.0001) Ford AC et al. Gut, Nov 2008; doi:10.1136/gut.2008.163162 2692

30. Antidepressant Receptor Site Effects NE 5HT Histamine Ach TCAs (25-150 mg) Amitriptyline (3o) +++ +++ ++++ ++++ Doxepin (3o) ++ +++ ++++ ++ Desipramine (2o) +++ +++ + + Nortriptyline (2o) +++ + ++ ++ SSRIs (1-2 pills) Citalopram nil ++++ nil nil Escitalopram nil ++++ nil nil Fluoxetine nil ++++ nil nil Paroxetine nil ++++ nil nil Sertraline nil ++++ nil nil SNRI’s (variable) Venlafaxine ++ ++ nil nil Duloxetine +++ +++ nil nil Milnacipran +++ ++ nil nil 1259a

31. Antidepressant considerations

32. Approach to prescribing antidepressants • Address false expectations or beliefs of patients • Provide psychopathological explanation of patient’s symptoms that psychopharmacological agent would target • Provide information/rationale aligned with patient’s interests/concerns • Negotiate treatment plan • Benefit in 4-6 weeks • Most side effects decrease in 1-2 weeks • Consider previous drugs that works and family history of drug response Drossman 2002

33. Gabapentin/pregabalin • Centrally acting agents with mechanism unclear. • ?centrally acting voltage-gated calcium channel modulators. • structurally similar to γ-amino butyric acid (GABA), which is a major inhibitory neurotransmitter in the CNS. • They reduce neuropathic pain by attenuating the release of many different neurotransmitters • Has few side effects and does not require serum monitoring. Taylor 2007; Gale & Houghton, 2011; Richard 2013

34. Other Central Agents with GI effects • Mirtazapine • Serotonergic and noradrenergic drug with 5HT2 and 5HT3 effects – can have pain benefit • Use with nausea, anorexia, weight loss, diarrhea • Some sedation • Clonidine • α2-adrenergic against with central (anxiety reduction) and peripheral (pain reduction via bowel compliance) • Helps reduce diarrhea • Prevents adrenergic effects of narcotic withdrawal • Buspirone • Azapirone with anti-anxiety effects acting on non BZD GABA receptors • Has 5HT1 and 5HT2 effects • Potential benefit for PDS (dyspepsia) due to receptive relaxation of stomach 2061

35. Quetiapine • Atypical antipsychotic with complex effects • Dopamine (D1 and D2) and Serotonin (5HT1a and 5HT2) antagonism with some α2-adrenergic blocking effect • Treatment Effects • Bipolar disorder and schizophrenia (labelling) • Augmentation for OCD, PTSD, depression • Sleep (normal sleep architecture) • Anxiety reduction • Some analgesic benefit • Improves painful FBD refractory to TCA or SNRI1 • Side effects • Sedation, somnolence, dry mouth • Metabolic syndrome (weight gain, glucose intolerance, hyperlipidemia) • Abnormal LFTs (rare) 1Grover M, Drossman DA. Dig Dis Sci 2009;54:1284 2062

36. Atypical Antipsychotic Quetiapine* in Refractory FGIDs 10/21 (48%) subjects discontinued Quetiapine 90 Significantly/somewhat better Same Worse 80 70 60 % Patient response 50 40 30 20 10 0 Bowel habits Global GI symptoms Abdominal pain *Dopamine (D1 and D2) and Serotonin (5HT1A and 5HT2) antagonism with some a2-adrenergic blocking effect Grover M, Drossman DA, et al. Dig Dis Sci 2009; 54:1284 2787

37. Potential Benefits of Supplemental Psychopharmacologic Agents CENTRAL ACTING PERIPHERAL ACTING Peripheral analgesic effects—alters visceral afferent signaling GI physiology (motility and secretion) via effects on neurotransmitter pathways Smooth muscle effects on viscera • Central pain perception—analgesia • Mood—anxiety, increased stress responsiveness • Treatment of associated psychiatric disorders—depression, PTSD, somatization • Treatment of associated sleep disturbances Grover & Drossman, 2011

38. Opioids (Narcotics) • Bind to CNS opioid receptors and inhibit release of pain neurotransmitters. • Mixed agonist/antagonists available • Many side effects –constipation, nausea, vomiting, sedation, pruritis, respiratory depression.

39. Opioids (narcotics) • Used acutely after surgical resection of the intestinal tract and to treat pain due to inflammation in IBD. • 5–13% of patients with IBD are on chronic narcotics in the outpatient setting. • Risk factors for outpatient narcotic use in IBD include psychiatric comorbidities (anxiety and depression), history of abuse, female gender, and a high degree of clinical symptoms • 20-70% inpatients with IBD use narcotics • Risk factors for inpatient narcotic use include diagnosis of CD, substance abuse, psychiatric factors, and the presence of IBS symptoms Edwards 2001; Cross 2005; Hanson 2009; Long 2011

40. Concerns with Opiates • Psychological/physical dependence • Higher rates of infection/mortality • Narcotic Bowel Syndrome (NBS) Grunkmeier 2007; Lichenstein 2006;

41. Typical Clinical Presentation for NBS • Chronic or recurrent abdominal pain which is treated with narcotics • Narcotics may have relieved pain initially but then stop working • Shorter pain-free periods result in increasing narcotic doses • Increasing doses further alter motility and aggravate pain • Can occur with in patients IBS, organic disease or otherwise health subjects (e.g., post operative) Grover & Drossman 2009; Long & Drossman; 2010

42. Risk of long-term opioid therapy • Loss of efficacy over time • Abnormal pain sensitivity (opioid induced hyperalgesia) • Aberrant drug-related behavior • Addiction, abuse and diversion • Increased risk of fracture • Cognitive impairment • Constipation • Abnormal immune function • Alterations of the reproductive system (opioid-induced testosterone deficiency) Grunkenheimer 2007 Drossman Center

43. There are safe ways to taper narcotics under appropriate medical care

44. Narcotic Withdrawal Protocol Accept pain as real and treatable Elicit patients concerns/expectations Provide information through a dialog Present the withdrawal program Gauge the patient’s response Clonidine 0.1mg PO q 6 hrs. Lorazepam 1mg PO q 6hrs. TCA or SNRI 220 200 180 160 140 120 100 80 60 40 20 0 Morphine equiv. Dose (mg) PEG 3350 17g PO BID Physician – Patient Relationship -3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 . . . 21 Day of taper Grunkemeier, DMS et al., Clin Gastroenterology and Hepatology 2007; 5:1126 1887

45. Abdominal Pain Scores 60 50 40 VAS (0-100) 30 20 10 0 Went back on narcotics n=10 Stayed off narcotics n=13 Pre-detox- ification n=39 Post-detox- ification n=37 Drossman DA et al. Am J Gastro 2012;107:1426 3 month follow-up 2574

46. Relationship of COMM Scores* to Detoxification and Responder Status Successful detoxification Successful Detoxification Responder Responder 2 p<0.06 p<0.02 1.5 1 Score 0.5 No. of subjects 29 4 20 12 0 Yes No Yes No *= Higher COMM scores indicates greater drug abuse potential Drossman DA et al. Am J Gastro 2012;107:1426 2591

47. Pain Management: Other therapies • Exercise • Complimentary alternative medicine (CAM) • Acupuncture • Yoga • Massage • Meditation • Support groups

48. Acupuncture • Postulated to have effects on acid secretion, GI motility and pain sensation via release of opiates in brain and body • Adults with IBS- no difference to sham procedure • Children with IBS or IBD- no support • Greater impact than placebo in children with chronic constipation Schneider Gut 2006; Lembo Am J Gastroenterol 2009; Broide Dig Dis Sci 2001

49. Summary Points • IBD is associated with psychopathology, functional pain, and maladaptive stress responses that increase morbidity, suffering, and costs. • Maximize treatment of underlying inflammation. • Integrated, personalized behavioral interventions to improve coping and decrease psychopathology can impact medical outcomes. • Pain medications as second line therapy • Better identification of risk factors for psychological stress can lead to prevention strategies.

50. The Drossman Center for the Education and Practice of Biopsychosocial Care Focused on improving healthcare by improving doctor-patient communications. With the DrossmanCare training, healthcare providers learn how to better communicate with patients to improve satisfaction and clinical outcomes. www.drossmancenter.com drossmangastroenterology.com