Evaluating and Treating Pain in IBD

Eva Szigethy MD, PHD

Associate Professor of Psychiatry, University of Pittsburgh Director, Medical Coping Clinic, Children’s Hospital of Pittsburgh

Director, Visceral Inflammation and Pain (VIP) CenterDivision of Gastroenterology, Hepatology, and Nutrition

December 12, 2013

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.

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

Binion et al., 2010

Relationship between pain and telephone encounters in adults with IBD

Ramos Rivers 2013

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

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 Ped Psychol 2012

Unrecognized inflammation in adults with quiescent IBD

Crohn’s Disease Ulcerative ColitisKeohane et al., Am J Gastroenterol 2010

Influences on Visceral Sensitization Stress

Abnormal inputs Repetitive bowel stimulation

Acute inflammation Infection IBD (mild or in remission)

Neurological trauma Operations Invasive procedures

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; 40:819Drossman DA et. al., Gastroenterology 2002

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

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

ABDOMINAL PAINPsychosocial

Life stressors ~ coping pain perception in IBD

Early life trauma linked to visceral hypersensitivity

Chronic stress reactivation risk

Ross et al. JPGN 2011Drossman. Am J Gastroenterol 2011Engstrom J Am Academ Child Adolesc Psych 1991Levenstein et al. Am J Gastroenterol 2000

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

Pain is a modifiable experience

Psychosocial Context

• Pain beliefs• Cultural• Expectation• Conditioning• Social support• Stress• Sleep

Injury• Peripheral and central

sensitization• Mechanical

Cognitions•Hypervigilance•Attention•Catastrophizing

Neurobiological•Neurodegeneration•Maladaptive plasticity

Genetics•Mutations•Gene products

Pain Experience

Nociceptive Modulation

Pain Management

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

Education: Offering a Validated Explanatory Model for Pain

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

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

Changes in Somatic Symptoms: CBT vs TAU

CDI Items

Anhedonia Sleep problems Fatigue Poor appetite Pain

% C

han

ge

in C

DI I

tem

Sco

res

PASCET-PI TAU

***

****

*

**

*

0

10

20

30

40

50

Szigethy et al., 2004,2007,2009

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

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

Hypnosis for IBDAdults •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)

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

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

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

Benefits of Psychological TreatmentBenefits of Psychological Treatment

22342234

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

Rationale for Antidepressants for IBDRationale for Antidepressants for IBD

12521252

Treatment of psychiatric co-morbidity

Peripheral effectsMotility / secretionAfferent

Central pain modulatory effects

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

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.

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 20/25 10.67 0.70 (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)

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 20/25 10.67 0.70 (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)

Ford AC et al. Gut, Nov 2008; doi:10.1136/gut.2008.163162 Ford AC et al. Gut, Nov 2008; doi:10.1136/gut.2008.163162

Overall Forest Plot of Antidepressant Studies for IBSOverall Forest Plot of Antidepressant Studies for IBS

Treatment Control RR (random) Weight RR (random)n/N n/N 95% CI % 95% CI

Treatment Control RR (random) Weight RR (random)n/N n/N 95% CI % 95% CI

Tricyclic Antidepressants (TCAs)Tricyclic Antidepressants (TCAs)

0.10.1 0.20.2 0.50.5 11 22 55 1010Favors treatmentFavors treatment Favors controlFavors control

Total events: 32 treatments; 153 controlsTest for heterogeneity: Chi2=10.94, df=8, (P=0.21), F=26.9%Test for overall effect: Z=3.86 (P=0.0001)

Total events: 32 treatments; 153 controlsTest for heterogeneity: Chi2=10.94, df=8, (P=0.21), F=26.9%Test for overall effect: Z=3.86 (P=0.0001)

26922692

NE 5HT Histamine AchTCAs (25-150 mg)

Amitriptyline (3o) +++ +++ ++++ ++++Doxepin (3o) ++ +++ ++++ ++Desipramine (2o) +++ +++ + +Nortriptyline (2o) +++ + ++ ++

SSRIs (1-2 pills)Citalopram nil ++++ nil nilEscitalopram nil ++++ nil nilFluoxetine nil ++++ nil nilParoxetine nil ++++ nil nilSertraline nil ++++ nil nil

SNRI’s (variable)Venlafaxine ++ ++ nil nilDuloxetine +++ +++ nil nilMilnacipran +++ ++ nil nil

NE 5HT Histamine AchTCAs (25-150 mg)

Amitriptyline (3o) +++ +++ ++++ ++++Doxepin (3o) ++ +++ ++++ ++Desipramine (2o) +++ +++ + +Nortriptyline (2o) +++ + ++ ++

SSRIs (1-2 pills)Citalopram nil ++++ nil nilEscitalopram nil ++++ nil nilFluoxetine nil ++++ nil nilParoxetine nil ++++ nil nilSertraline nil ++++ nil nil

SNRI’s (variable)Venlafaxine ++ ++ nil nilDuloxetine +++ +++ nil nilMilnacipran +++ ++ nil nil

Antidepressant Receptor Site Effects

1259a

Antidepressant considerations

TCA SSRI SNRIPotential benefits Pain

DepressionPainDepressionAnxiety

Pain Depression

Adverse effects Sedation ConstipationHypotensionDry mouthArrhythmiaWeight gain

AgitationDiarrheaNight sweatsHeadacheSexual dysfunction

NauseaAgitationDizzinessSleep disturbanceFatigueLiver dysfunction

Overdose Risk Moderate Minimal Minimal

Cost/month $5-30 $40-80 $60-100

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

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

Mirtazapine Serotonergic and noradrenergic drug with 5HT2 and 5HT3 effects – can have pain benefitUse with nausea, anorexia, weight loss, diarrheaSome sedation

Clonidineα2-adrenergic against with central (anxiety reduction) and peripheral (pain reduction via bowel compliance)Helps reduce diarrheaPrevents adrenergic effects of narcotic withdrawal

BuspironeAzapirone with anti-anxiety effects acting on non BZD GABA receptorsHas 5HT1 and 5HT2 effectsPotential benefit for PDS (dyspepsia) due to receptive relaxation of stomach

Other Central Agents with GI effects

20612061

QuetiapineAtypical antipsychotic with complex effectsDopamine (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)

206220621Grover M, Drossman DA. Dig Dis Sci 2009;54:12841Grover M, Drossman DA. Dig Dis Sci 2009;54:1284

Atypical Antipsychotic Quetiapine*Atypical Antipsychotic Quetiapine*in Refractory FGIDsin Refractory FGIDs

27872787

10/21 (48%) subjects discontinued Quetiapine10/21 (48%) subjects discontinued Quetiapine

Grover M, Drossman DA, et al. Dig Dis Sci 2009; 54:1284** Dopamine (DDopamine (D11 and D and D22) and Serotonin (5HT) and Serotonin (5HT1A1A and 5HT and 5HT22) antagonism with some ) antagonism with some 2-adrenergic blocking effect2-adrenergic blocking effect

Global GIGlobal GIsymptomssymptoms

AbdominalAbdominalpainpain

BowelBowelhabitshabits

%%Patient Patient

responseresponse

0

10

20

80

90

70

50

40

60

30

Significantly/somewhat betterSignificantly/somewhat betterSameSameWorseWorse

Potential Benefits of Supplemental Psychopharmacologic Agents

CENTRAL ACTING• Central pain perception—

analgesia

• Mood—anxiety, increased stress responsiveness

• Treatment of associated psychiatric disorders—depression, PTSD, somatization

• Treatment of associated sleep disturbances

PERIPHERAL ACTING• Peripheral analgesic effects—

alters visceral afferent signaling

• GI physiology (motility and secretion) via effects on neurotransmitter pathways

• Smooth muscle effects on viscera

Grover & Drossman, 2011

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.

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

Concerns with Opiates

• Psychological/physical dependence

• Higher rates of infection/mortality

• Narcotic Bowel Syndrome (NBS)

Grunkmeier 2007; Lichenstein 2006;

Typical Clinical Presentation for NBSTypical 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)

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

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 2007Drossman Center

There are safe ways to taper narcotics under appropriate medical care

Narcotic Withdrawal Protocol

Accept pain as real and treatableElicit patients concerns/expectationsProvide information through a dialogPresent the withdrawal programGauge the patient’s response

Physician – Patient Relationship

PEG 3350 17g PO BID

TCA or SNRI

Lorazepam 1mg PO q 6hrs.

Clonidine 0.1mg PO q 6 hrs.

-3 -2 -1 0 1 2 3 4 5 6 7 8 9 10 . . . 21Day of taper

Morphine equiv. Dose (mg) 220 200 180 160 140 120 100 80 60 40 20 0

18871887Grunkemeier, DMS et al., Clin Gastroenterology and Hepatology 2007; 5:1126

Abdominal Pain Scores

25742574

6060

5050

3030

1010

00Stayed offnarcotics

n=13

Stayed offnarcotics

n=13

VAS(0-100)VAS

(0-100)

4040

2020

Went back onnarcotics

n=10

Went back onnarcotics

n=10

Pre-detox-ification

n=39

Pre-detox-ification

n=39

Post-detox-ification

n=37

Post-detox-ification

n=37

3 month follow-up3 month follow-upDrossman DA et al. Am J Gastro 2012;107:1426

25912591

ScoreScore

Relationship of COMM Scores* to Detoxification and Responder Status

0

0.5

1

1.5

2

Successfuldetoxification Responder

* = Higher COMM scores indicates greater drug abuse potential

Yes No Yes No

p<0.06 p<0.02

29 4 20 12No. of subjects

Drossman DA et al. Am J Gastro 2012;107:1426

Successful Detoxification Responder

Pain Management: Other therapies

• Exercise• Complimentary alternative medicine (CAM)

– Acupuncture– Yoga– Massage– Meditation

• Support groups

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

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.

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.comdrossmangastroenterology.com

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Dynamic- interpersonal

psycho Rx

Augumentation Therapy

● Two different antidepressants● Antidepressant + non-pharmacological Rx● Antidepressant + atypical antipsychotic● Antidepressant + anticholinergic● Antidepressant + Pregabalin or Gabapentin

Cognitive behavioral Rx

Hypnosis Antidepressants Symptomatic Rx

Non-pharmacologic

Rx

Pharmacologic Rx

Patient-physicianTherapeutic relationship

Sperber A and Drossman D, Alim Pharm Ther 2011;33:514Sperber A and Drossman D, Alim Pharm Ther 2011;33:514

T52

Diet, lifestyle advice Positive diagnosis Explain, reassure

Diet, lifestyle advice Positive diagnosis Explain, reassure

Narcotic withdrawal Multidisciplinary approach Psychological treatments Central treatments

Narcotic withdrawal Multidisciplinary approach Psychological treatments Central treatments

Graded Multi-Component TreatmentGraded Multi-Component Treatment

Severe

Moderate

Mild

++

++ Manage stress Gut treatments Manage stress Gut treatments