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Lessons from Neurobiology : Understanding the Overlap between Pain and Mood Disorders

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. Let’s Ask (and Answer) Three Questions.

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Lessons from Neurobiology : Understanding the Overlap between Pain and Mood Disorders

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  1. LessonsfromNeurobiology: Understanding the Overlapbetween Pain and MoodDisorders Rakesh Jain, MD, MPH R/D Clinical Research, Inc. Lake Jackson, Texas, USA Texas Tech Health Sciences Center – Permian Basin Midland, Texas, USA

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

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

  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.

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

  6. Pain Condition (Headaches) and Depression/Anxiety *P<0.05 * * * 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.

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

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

  9. Chronic Pain After Accidental Injury and its Relationship to Depression and Anxiety (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 Jenewein J, et al. J Psychosom Res. 2009;66:119-126.

  10. Dose-Response Curve Exists Between Chronic Pain and Psychiatric Difficulties *P<0.001 * * HADS Anxiety Sub-scale Mean Scores (s score range 0–21) 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.

  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.

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

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

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

  15. The “Pain Matrix” 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 Regional Interactions Cognitive/Integrative Regions Prefrontal cortex Temporal lobe Parietal cortex Modulatory Regions Midbrain (PAG, NCu) Cortical regions Paphe nucleus Subcortical regions 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. Borsook D, et al. Neuroscientist. 2010;16(2):171-185.

  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.

  17. 100.0 R2=0.57 50.0 Relaxation Sadness Anger Fear and Anxiety Relief Satisfaction 10.0 20.0 –20.0 –10.0 –50.0 –100.0 Negative Emotions Robustly Increased Pain and Autonomic Response Change in Pain/Unpleasantness (Emotion Baseline) Change in Emotion (Emotion-Baseline) (Emotions hypnotically induced) N=26. Rainville P, et al.Pain 2005;118:306-318.

  18. Primary nociceptive afferents (-) BRAINSTREAM MIDBRAIN (-) PSTT (-) (+) (+) (+) CORTICO- LIMBIC INPUT GABA INTER-NEURON SPINAL INTER-NEURON NRM 5-HT PAG OPIOIDS RMC NE (+) (-) (+) DLF 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.

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

  20. Red = inhibitory pathway Green = stimulatory pathway Shared Neuroendocrine and Neuroimmune Dysregulation 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.

  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.

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

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

  24. Pain Autonomic Nervous System Cytokines Potential Clinical Consequences of Relationship of Pain to HPA, Pro-inflammatory Cytokines, and the Autonomic System 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. Potential consequences of such dysregulation: Fatigue Sleep impairment Depressed mood and anhedonia Difficulty concentrating Anxiety and irritability Appetite and libido disturbances

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

  26. And the consequences of this overlap are …

  27. Immunologic Impact of Pain With Increasing Duration of Pain * *P<0.001 Catechols, Neurokinin K Increased sympathetic activity Substance P IL-6 Sympathetic mediated pain IL-8 IL-IRa Hyperalgesia, fatigue, depression * • 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 n=23 n=23 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.

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

  29. GM Loss in Pain – in Regions Also Involved With Anxiety Regulation * *P<0.001 * Volume (mm3) • 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 cm3 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.

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

  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.

  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

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

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

  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.

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

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

  38. Long-term Benefits of Psychotherapy in FM (12-Month Follow-up Data) Cognitive Behavioral Therapy (CBT) Operant Behavioral Therapy (OBT) AttentionPlacebo (AP) -60 -40 -20 0 20 40 60 % of Patients Reporting 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.

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

  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.

  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.

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

  43. CBT: How Effective Is It? For Which Symptoms of FM Is It Effective? Effect Size 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” Bernardy K, et al. J Rheumatol. 2010;37(10):1991-1205.

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

  45. Relationship Between Pain, Pain Severity, and Sleep • 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 Silverman S, et al. BMC Musculoskelet Disord. 2010;11:66.

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

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

  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.

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

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

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