1. Lessons from Neurobiology: Understanding the Overlap between Pain and Mood Disorders Rakesh Jain, MD, MPH R/D Clinical Research, Inc. Lake Jackson, Texas, USA Texas Tech Health Sciences Center – Permian Basin Midland, Texas, USA 1

2. Let’s Ask (and Answer) Three Questions 1.Is there a link between chronic pain and depression 2.Why is there a link between chronic pain and depression? 3.What do we do about this chronic pain and depression link? 2

3. 1. Is there a link between Chronic Pain and Depression 3

4. Lifetime Prevalence of Mental Illnesses is High Risk of any disorder:46.4 % 2 or more disorder: 27.7 % 3 or more disorders:17.3 % Kessler RC, et al. Arch Gen Psychiatry. 2005;62:593-602. 4

5. Is Pain Impacted by the Co-occurrence of Psychiatric Disorders? Brief Pain Inventory Pain Score (mean) range: 0-10 * * * * * * *P<0.001 Bair MJ, et al. Psychosom Med. 2008;70:890-897. 5

6. Pain Condition (Headaches) and Depression/Anxiety 6 Weighted 12 month adjusted odds ratio of association between severe headaches or migraine and mental disorders Adjusted odds ratio (adjusted for age, race, sex, and educational status). Kalaydjain A, Merikangas K. Psychosom Med. 2008;70:773-780. *P<0.05 * * *

7. “Ring of Fire”: Odds Ratio of Psychiatric Comorbidities in Fibromyalgia FibromyalgiaFibromyalgia Any Anxiety Disorder 6.7 6.7 Eating Disorder 2.4 2.4 Substance Use Disorder 3.3Substance 3.3 Major Depression 2.7 2.7 Arnold LM, et al. J Clin Psychiatry. 2006;67:1219-1225. 7

8. BPI – DPN Average Pain Severity Mean score DPNP Patients: Relationship Between Pain and Mental Disorders * * * * *P<0.01 Gore M, et al. J Pain Symptom Manage. 2005;30(4):374-385. 8

9. (HADS-Depression score) *P<0.05 3 years later: 45% had chronic pain 3 years after accident: 4.4% developed PTSD >10% developed subsyndromal PTSD All but one patient with PTSD (full or sub-syndromic) had chronic pain Chronic Pain After Accidental Injury and its Relationship to Depression and Anxiety Jenewein J, et al. J Psychosom Res. 2009;66:119-126. 9

10. HADS Anxiety Sub-scale Mean Scores (s score range 0–21) *P<0.001 Dose-Response Curve Exists Between Chronic Pain and Psychiatric Difficulties * * N=448. HADS=Hospital Anxiety and Depression Scale; NPAD-d=Neck Pain and Disability Scale German Version. Blozik E, et al. BMC Musculoskelet Disord. 2009;10(13):1-8. 10

11. Do Anxiety, Depression, or Sleep Problems Predict the Development of Pain? 15 month prospective study, 3171 followed, 324 developed chronic widespread pain Gupta A, et al. Rheumatology. 2007;46:666-671. 11

12. In Conclusion to Question 1: Is there a link between Chronic Pain and Depression? Answer: Yes! And it’s a strong link… 12

13. 2. Why is there a link between chronic pain and depression? 13

14. The Pain Circuit Involves Sensory, Emotional, and Cognitive Regions of the Brain Fast, myelinated A-fibers Slow, unmyelinated C-fibers Somatosensory cortex Thalamus Limbic system Cerebrum Brainstem Spinal cord Spinothalamic tract Dorsal ganglion Afferent nerve fiber Adapted from Giordano J. Pain Physician. 2005;8:277-290. 14

15. The “Pain Matrix” A=amygdala; ACC=anterior cingulate cortex; Cer=cerebellum; H=hypothalamus; Ins=insula; l, m=lateral and medial thalamus; M1=primary motor cortex; NA=nucleus accumbens; PAG=periaqueductal gray; PFC=prefrontal cortex; PPC=posterior parietal cortex; S1, S2=primary and secondary somatosensory cortex; SMA=supplementary motor area. Sensory-Motor Regions Primary sensory and motor cortices Thalamus Posterior insula Sensory-Motor Regions Primary sensory and motor cortices Thalamus Posterior insula Emotional/Affective Regions Anterior cingulate Accumbens Posterior cingulate Hippocampus Orbitofrontal cortex Thalamus Medial prefrontal cortex Amygdala Anterior insula Caudate Emotional/Affective Regions Anterior cingulate Accumbens Posterior cingulate Hippocampus Orbitofrontal cortex Thalamus Medial prefrontal cortex Amygdala Anterior insula Caudate Cognitive/Integrative Regions Prefrontal cortex Temporal lobe Parietal cortex Cognitive/Integrative Regions Prefrontal cortex Temporal lobe Parietal cortex Modulatory Regions Midbrain (PAG, NCu) Cortical regions Paphe nucleus Subcortical regions Modulatory Regions Midbrain (PAG, NCu) Cortical regions Paphe nucleus Subcortical regions Regional Interactions Borsook D, et al. Neuroscientist. 2010;16(2):171-185. 15

16. A Closer Look at Shared Anatomy: Complex Circuits Involve Sensory, Cognitive, and Emotional Regions Apkarian AV, et al. Eur J Pain. 2005;9:463-484. 16

17. Negative Emotions Robustly Increased Pain and Autonomic Response Change in Emotion (Emotion-Baseline) Change in Pain/Unpleasantness (Emotion Baseline) Relaxation Sadness Anger Fear and Anxiety Relief Satisfaction –50.0 50.0 100.0 –100.0 –20.0 –10.0 20.010.0 R 2 =0.57 (Emotions hypnotically induced) N=26. Rainville P, et al. Pain 2005;118:306-318. 17

18. CORTICO- LIMBIC INPUT PAG OPIOIDS RMC NE DLF NRM 5-HT SPINAL INTER- NEURON MIDBRAINBRAINSTREAM Primary nociceptive afferents (+) (-) (+) (-) PSTT GABA INTER- NEURON Many Neurotransmitters are Shared by Pain and Depression (+) 5-HT=5-hydroxytryptamine; DLF=dorolateral funiculus; NRM=nucleus raphe mangus; RMC=reticular magnocellular nuclei; PAG=periaqueductal grey substance; PSTT=paleospinothalic tract. Giordano J. Pain Physician 2005;8:277–90. 18

19. Pain and Depression: a Deeper Examination Focus on: –HPA –Inflammatory cytokines –Autonomic nervous system HPA=hypothalamic-pituitary axis. 19

20. Shared Neuroendocrine and Neuroimmune Dysregulation Red = inhibitory pathway Green = stimulatory pathway 1. Raison CL, et al. Trends Immunol. 2006;27:24-31. 2. Nestler EJ, et al. Neuron. 2002;34:13-25. 3. Blackburn-Munro G, Blackburn-Munro RE. J Neuroendocrinol. 2001;13:1009-1023. 20

21. Stress/Inflammation Link: a True Mind- Body (and Circular) Relationship CRH=corticotropin-releasing hormone; NF-κB=nuclear factor kappa B; ACTH=adrenocorticotropic hormone. Miller AH, et al. Biol Psychiatry. 2009;65:732-741. 21

22. Autonomic Dysregulation May Augment Pain P <.05 P =NS n=20 Norepinephrine-evoked pain -2 0 1 2 3 4 5 6 7 8 9 10 FMRAHC (norepinephrine-placebo) n=20 P≤0.05 P=NS 16/206/20 56.3% 94.3% 54.3%11.9% 11.9% Visual analog scale Martinez-Lavin M, et al. BMC Musculoskelet Disord. 2002;3:2. 22

23. A Comprehensive, Neurobiological View of Pain and Psychology Jain R, et al. Curr Diab Rep. 2011;11:275-284. 23

24. Potential Clinical Consequences of Relationship of Pain to HPA, Pro-inflammatory Cytokines, and the Autonomic System Potential consequences of such dysregulation: Fatigue Sleep impairment Depressed mood and anhedonia Difficulty concentrating Anxiety and irritability Appetite and libido disturbances Kim YK, et al. Prog Neuropsychopharmacol Biol Psychiatry. 2007;31:1044-1053. Raison CL, et al. CNS Drugs. 2005;19:105-123. Dantzer R. Neurol Clin. 2006;24:441-460. 24

25. How Pain and Psychiatric Difficulties Get Tied Together by Neurobiology Tracey I, Dickenson T. Cell. 2012;148:1308-1308, e2. 25

26. And the consequences of this overlap are … 26

27. Immunologic Impact of Pain With Increasing Duration of Pain IL-8 is a proinflammatory cytokine, mediates sympathetic pain IL-Ra is involved with stress IL-6 is involved with stress, fatigue, hyperalgesia, depression, and it activates sympathetic pain Substance P Increased sympathetic activity Hyperalgesia, fatigue, depression Sympathetic mediated pain IL-6 IL-8 IL-IRa Catechols, Neurokinin K n=23 * *P<0.001 * Patients met ACR criteria for FM. Wallace DJ, et al. Rheumatology. 2001:40:743-749. Schwartz YA, et al. Am J Resp Cell Mol Biol. 1999;21:388-394. 27

28. Patients with chronic back pain (CBP) had 5%–11% less whole brain gray matter, equivalent to 10–20 years of normal aging Back Pain Patients may Experience Gray Matter Atrophy in Areas Involved With Cognition and Emotional Regulation Apkarian AV et al. J Neurosci. 2004;24(46):P10410-P10415. 28

29. GM Loss in Pain – in Regions Also Involved With Anxiety Regulation *P <0.001 Volume (mm 3 ) Patients with FM (n=10) had significantly less GM volume in posterior cingulate, insular cortex, MFC, and parahippocampal gyrus Rate of age-related decline was significantly greater in patients with FM than in controls (n=10; P<0.001) Patients with FM were losing 10.5 cm 3 of GM annually since year of their diagnosis * * C=controls; CSF=cerebrospinal fluid; GM=grey matter; WM=white matter; MFC=medical frontal cortex. Kuchinad A, et al. J Neurosci. 2007;27:4004–4007. 29

30. FM – AD = 29 FM + AD = 29 HC = 29 R = –0.47 P<0.002 Pain and Brain Volume Changes When Comorbid with Depression or Anxiety GMV=gray matter volume; TIV=total intracranial volume; STPI=State-Trait Personality Inventory Hsu MC, et al. Pain. 2009;143(3):262-267. 30

31. Chronic Pain (Low Back Pain) Impacts the Brain (Same Regions Shared With Mood/Anxiety Control) Cortical thickness in CLBP patients (n=18) compared with controls (n=16) Random-field theory-based cluster-corrected P<0.05 maps Blue areas represent clusters that are significantly thinner in CLBP patients than controls Seminowicz DA, et al. J Neurosci. 2011;31(20):7540-7550. 31

32. In Conclusion to Question 2: Why is there a link between chronic pain and depression? Answer: For multiple reasons: Shared anatomy Shared chemistry Shared pathways that connect the mind and body, are a few reasons for such a link 32

33. 3. What do we do about this chronic pain and depression link? 33

34. First: We use Neurobiology to Understand our Treatment Options Tracey I, Dickenson T. Cell. 2012;148:1308-1308, e2. 34

35. Recommendations from the British Pain Society Experts from the BPS Consensus Guidelines in Pain Management in Adults “Pain management programmes based on cognitive behavioural principles, are the treatment of choice…” “Evaluation of outcomes should be standard practice, assessing distress/emotional impact of pain…” BPS Recommended Guidelines for Pain Management Programmes for Adults, Consensus Statement, April 2007. 35

36. N=41; data for individuals completing 6-month follow-up *P<0.05 Six weekly 90-minute group sessions Based on CBT Attention management manual * Cognitive Behavioral Management of Chronic Pain Elomaa MM, et al. Eur J Pain. 2009;13(10):1062-1067. 36

37. Change from Baseline Scores CES-D STAIBPI-Interference Mind-Body Intervention for Older Adults with Chronic Pain Berman RLH, et al. J Pain. 2009;10(1):68-79. 37

38. Long-term Benefits of Psychotherapy in FM (12-Month Follow-up Data) % of Patients Reporting -60-40-200204060 Attention Placebo (AP) Operant Behavioral Therapy (OBT) Cognitive Behavioral Therapy (CBT) Clinically significant reduction in pain Clinically significant increase in pain N=125: CBT: n=42; OBT: n=43; AP: n=40. Thieme K, et al. Arthritis Rheum. 2007;57(5):830-836. 38

39. Psychoeducation Relaxation training Behavioral pacing Relapse prevention Realistic goal setting Identifying dysfunctional thought patterns Communication skills training Key Elements of Cognitive Behavioral Therapy Bennett R, et al. Nat Clin Pract Rheumatol. 2006;2(8):416-424. 39

40. Physical Fitness in Individuals With Chronic Pain In physical self-report or functional testing, the average 40-year-old patient who has FM was found to be as physically unfit as an 80-year-old person who does not have FM Rutledge DN, et al. J Nurs Scholarsh. 2007;39(4):319-324. Shillam CR, et al. Arthritis Rheum. 2009;58(suppl 9):1408. 40

41. Top 10 Principles for Prescribing Exercise Treat peripheral pain generators to minimize central sensitization Minimize eccentric muscle work Program low-intensity nonrepetitive exercise Recognize importance of restorative sleep Screen for and treat autonomic dysfunction Evaluate for poor balance and risks for falling Modify exercise for common comorbidities Address obesity and deconditioning Conserve energy in daily life to exercise Promote self-efficacy Jones KD, et al. Rheum Dis Clin N Am. 2009;35(2):373-391. 41

42. Aerobic Performance Tender Point Pain Pressure Threshold Improvement in Pain Improvement (%)Worsening (%) -1.6 -7.0 0.5 11.4 28.1 17.1 Control group Exercise intervention group Exercise: a Meta-analysis of Studies 0 Busch AJ, et al. Cochrane Database Syst Rev. 2002;(3):CD003786. 42

43. CBT: How Effective Is It? For Which Symptoms of FM Is It Effective? A total of 14 out of 27 RCTs with 910 subjects with a median treatment time of 27 hours (range: 6-75) over a median of 9 weeks (range: 5-15) were included “... the high grade of recommendation given to CBT in the American and German guidelines on FM needs to be reconsidered” Effect Size Bernardy K, et al. J Rheumatol. 2010;37(10):1991-1205. 43

44. Tai Chi in Chronic Pain: Demonstrated Effectiveness of a Mind-Body Intervention Tai Chi group, n=33 Control group, n= 33 12 weeks, twice weekly, 60-minute Tai Chi sessions vs wellness education and stretching FIQ = FM impact questionnaire. FIQ at 12 weeks (P<0.001) Improvements were maintained at 24 weeks (P<0.001) Chenchen W, et al. N Engl J Med. 2010;363(8):743-754. 44

45. Relationship between self-reported FM severity and current pain (A) and pain-related sleep interference (B) Values represent mean scores from short form of modified Brief Pain Inventory P-values are for overall association between FM severity and levels of current pain and pain-related sleep interference using ANOVA Relationship Between Pain, Pain Severity, and Sleep Silverman S, et al. BMC Musculoskelet Disord. 2010;11:66. 45

46. Pharmacological Treatment Options for Anxiety and Mood Disorders TCAs (many) Venlafaxine Duloxetine Desvenlafaxine milnacipran 46

47. 3 weeks of multidisciplinary treatment consisted of education, stretching, CBT, relaxation training, and aerobic exercise Multidisciplinary Treatment: Impact on Improvement and HPA Changes N=12. CBT=cognitive behavioral therapy; CES-D=Center for Epidemiologic Studies Depression Rating Scale. Bonifazi M, et al. Psychoneuroendocrinology. 2006;31:1076-1086. Before admission and treatment Before treatment After treatment 64.1 57.3 22.4 5.5 48.9 38 13.3 63.1 24.9 69 13.5 13.3 VAS Score (1-100) % of Pain Area CES-D Score (0-60) * * * * * P<0.05 Positive Tender Points (n) 47

48. If Treatment of Pain Succeeds, Then There is Positive Impact on the Brain – This is Good News Indeed! t- and p-value maps for patients who responded to treatment (n=11) showing that the left DLPFC became thicker in patients after treatment compared with before treatment (arrow) Seminowicz DA, et al. J Neurosci. 2011;31(20):7540-7550. 48

49. A Suggested Clinical Pathway to Managing Depression in a Patient with Pain 49

50. Scales for Diagnosing Anxiety and Depression HADS PHQ-9 GAD-7 50

51. A Clinically Useful Anxiety Screener: GAD-7 Kroenke K, et al. Ann Intern Med. 2007;146:317-325. 51

52. GAD-7 Score of ≥8 GAD-7: Useful in Detecting Multiple Anxiety Disorders Kroenke K, et al. Ann Intern Med. 2007;146:317-325. 52

53. GAD-7 How to Use Patients circle one of the 4 numbers (representing severity) associated with 7 problems If patients identify any problems, they then indicate (by checking the appropriate box) the degree to which these problems made it difficult for them to work, take care of home responsibilities, or get along with people How to Use Patients circle one of the 4 numbers (representing severity) associated with 7 problems If patients identify any problems, they then indicate (by checking the appropriate box) the degree to which these problems made it difficult for them to work, take care of home responsibilities, or get along with people 53

54. How to Use Brief, 9-item self-report screening tool to help identify symptoms that could relate to depression Developed for use in primary care settings How to Use Brief, 9-item self-report screening tool to help identify symptoms that could relate to depression Developed for use in primary care settingsPHQ-9 54

55. PHQ-9 How to Score Major depressive syndrome is suggested if: Of the 9 items, 5 or more are circled as at least “More than half the days” Either item 1a or 1b is positive, that is, at least “More than half the days” Minor depressive syndrome is suggested if: Of the 9 items, b, c, or d are circled as at least “More than half the days” Either item 1a or 1b is positive, that is, at least “More than half the days” How to Score Major depressive syndrome is suggested if: Of the 9 items, 5 or more are circled as at least “More than half the days” Either item 1a or 1b is positive, that is, at least “More than half the days” Minor depressive syndrome is suggested if: Of the 9 items, b, c, or d are circled as at least “More than half the days” Either item 1a or 1b is positive, that is, at least “More than half the days” Add all circled answers. For every answer circled : Not at all = 0 Several Days = 1 More than half the days = 2 Nearly every day = 3 Add all circled answers. For every answer circled : Not at all = 0 Several Days = 1 More than half the days = 2 Nearly every day = 3 Pfizer Inc. Instructions for Use (for doctor or healthcare professional use only): PHQ-9 Quick Depression Assessment. Available at: http://www.phqscreeners.com/pdfs/PHQ9InstruxforUse.pdf.; The MacArthur Initiative on Depression and Primary Care at Dartmouth and Duke. Depression Management Tool Kit. Hanover, NH: Trustees of Dartmouth College, 2004. 55

56. In Conclusion: 56

57. Optimum would be early, full, and sustained control over ALL symptoms Pain Sleep Fatigue Cognitive Metabolic 57

58. What Are We Treating When We “Treat” a Patient ? Cognitive disturbance FatigueFatigue Sleep disturbance PainPain Metabolic syndrome 58

59.  Educate, educate, educate  Reassure, reassure, reassure  Start slow, go slow titration schedule  “Off-label” titration often employed and often appropriate  Aggressively manage early adverse effects  Pseudo or false failure of medication trials is common  It is because of several reasons patients appear to be unusually sensitive to medication adverse effects  Catastrophizing is a known psychological trait of patients  We clinicians often tend to start patients on too aggressive a titration schedule Encountering, and Conquering “Pseudo- medication” Failure 59

60. Target Symptoms and Shared Neurobiology of Chronic Pain and Depression Genetic predisposition Neuroendocrine- immune dysfunction CSSCSS ANS dysfunction Poor sleep TraumaTrauma Psychological factors, stress Infections, Inflammation Neonatal, Childhood trauma OtherfactorsOtherfactors Hyperexcitement of central neurons Environmental, Chemical CentralsensitizationCentralsensitization Central sensitization Other mechanisms Yunus MB. Semin Arthritis Rheum. 2007;36:339-356. 60

61. Four Things to Keep in Mind 1.“Abnormal” psychological problems – such as anxiety and depression, are very common in pain conditions 2.This creates a bi-directional, “spiral down” negative impact on the pain patient 3.Multiple links exist between pain and psychological issues – neuro-endocrine, neuro-inflammation, autonomic disruptions, etc 4.Treatment – Pain outcomes are negatively impacted if psychological issues are not well identified (thankfully, reverse is equally true!) 61