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Rakesh Jain, USA

“ Divided No More” Neurobiologic Mind-Body Unification of Depression/ Anxiety/ Insomnia & Chronic Pain. Rakesh Jain, USA.

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Rakesh Jain, USA

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  1. “Divided No More”Neurobiologic Mind-Body Unification of Depression/ Anxiety/ Insomnia&Chronic Pain Rakesh Jain, USA

  2. The information presented herein has been developed by a third party independent from Pfizer, Pfizer does not necessarily share or endorse the information contained herein, and it is not responsible for the opinions, images, pictures, videos or any other material contained herein or for the accuracy or parameters of such presentation. Pfizer did not participate in the development of the content of this presentation.

  3. Anxiety & Depressive D/Os are Very Common Clusters of Psychiatric Disorders 28.8% 24.8% 20.8% 14.6% N = 9,282 50% 40% 30% 20% 10% 0% Substance Use Mood Disorder Impulse-Control Anxiety Disorder Disorder Disorder Kessler RC et al. Arch Gen Psychiatry. 2005;62:593-602.

  4. Pain Condition (Headaches) and Anxiety Disorders Weighted 12-month adjusted odds ratio of association between severe headaches or migraine with mental disorders * * * * p<0.05 Adjusted odds ratio (adjusted for age, race, sex & educational status) Kalaydjian AK et al. Psychosom Med 2008;70:773-80

  5. Neck Pain & Anxiety – Increasing Pain Predicts Increasing Anxiety N=448 * p<0.001 HADS Anxiety Sub-scale Mean Scores (s score range 0-21) HADS – Hospital Anxiety and Depression Scale NPAD-d – Neck Pain and Disability Scale German Version Blozik E et al. BMC Musculoskel Dis 2009;10:13

  6. “Ring of Fire”: Odds Ratio of Psychiatric Comorbidities in FM N = 108 with fibromyalgia, 228 without 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 ClinPsychiatry 2006;67:1219-25

  7. DPNP Patients – Relationship Between Pain & Mental Disorders * N = 255 * * Score BPI – DPN Average Pain Severity HADS = Hospital Anxiety and Depression Scale BPI = Brief Pain Inventory Gore M et al. J Pain Symptom Manage 2005;30(4):374-85

  8. Is Pain Affected by the Co-occurrence of Anxiety and/or Depression ? * 8 Pain only (n=271) * * 7 * * * 6 Pain + Anxiety (n=15) 5 Brief Pain Inventory Pain Score (mean) range : 0-10 Pain + Depression (n=98) 4 3 Pain + Anxiety + Depression (n=116) 2 1 *p<0 .001 Pain Severity Pain Interference Bair MJ et.al. Psychosom Med 2008;70:890-897

  9. Chronic Pain after Accidental Injury & Its Relationship to Anxiety / Depression * 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 * * JeneweinJ et al. J Psychosom Res 2009;66:119-26

  10. Do Anxiety, Depression, or Sleep Problems Predict the Development of Pain? Odds ratio Odds ratio Depression(HADS Depression sub-score) Anxiety(HADS Anxiety sub-score) 15-month prospective study, 3171 followed, 324 developed chronic widespread pain Odds ratio Sleep(Sleep Problem Scale) Gupta A et al. Rheumatology 2007;46:666-71

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

  12. Anxiety Severity and its Relationship to Pain State anxiety Trait anxiety 10 8 6 VAS(Visual Analog Scale) 4 2 0 20 30 40 50 60 70 Pain severity related to state anxiety (r=.2706, P>0.05) and trait anxiety (r=.3328, P<0.05) inventory scores Celiker R et al. ClinRheumatol1997;16:179-84

  13. The Pain Circuit Involves Sensory, Emotional, and Cognitive Regions of the Brain Somatosensory cortex Limbic system Cerebrum Thalamus Brainstem Slow, unmyelinated C-fibers Spinal cord Spinothalamic tract Dorsal ganglion Fast, myelinatedA-fibers Afferent nerve fiber Adapted from Giordano J. Pain Physician 2005;8:277-90

  14. Shared Anatomy: Complex Circuits Involve Sensory, Cognitive, and Emotional Regions Apkarian AV et al. Eur J Pain 2005;9:463-84

  15. S1 S2 ACC Insula Thal PFC VS Hippo AMG Dorsal root ganglion OFC Hyp PAG PB Pain Pain and Anxiety/ Depression have a Strongly Shared Neuroanatomy ACC, anterior cingulate cortex; AMG, amygdala; DS, dorsal striatum; Hippo, hippocampus; Hyp, hypothalamus; Insula, insular cortex; OFC, orbitofrontal cortex; PAG, periaqueductal grey; PB, parabrachial nucleus; PFC, prefrontal cortex; S1, S2, somatosensory cortex; Thal, thalamus; VS, ventral striatum. Shurman J, et al. Pain Med. 2010;11:1092-1098

  16. The “Pain Matrix”: The Reason Why So Many Pain Patients have Multiple Symptoms Sensory-Motor Regions Primary sensory and motor cortices Thalamus Posterior insula Emotional/Affective Regions Regional Interactions Cognitive/Integrative Regions Prefrontal cortex Temporal lobe Parietal cortex Modulatory 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):171-85

  17. Brain Areas Involved in Pain Processing – “Divided No More” Borsook D, et al. Mol Pain2007;3:25.

  18. In Pain Patients - Brain Perfusion Studies Implicate Anxiety Regulatory Centers Bilateral parietal perfusion (BA7) Bilateral post-central perfusion (BA4) Left anterior temporal perfusion Negative correlation Positive correlation GuedjE et al. J Nucl Med 2008;49;11:1798-1803

  19. Many Neurotransmitters Are Shared by Pain & Anxiety Primary nociceptive afferents (-) (-) PSTT BRAINSTREAM MIDBRAIN (+) (-) (+) (+) (+) CORTICO- LIMBIC INPUT GABA INTER-NEURON SPINAL INTER-NEURON NRM 5-HT PAG OPIOIDS RMC NE (+) (-) (+) DLF 5-HT=5-hydroxytryptamine; DLF=dorolateralfuniculus; NRM=nucleus raphemangus; RMC=magnocellularnuclei; PAG=periaqueductal grey substance; PSTT=paleospinothalic tract. Giordano J. Pain Physician 2005;8:277-290

  20. Back Pain: 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 ApkarianAV et.al. J Neurosci2004;24(46):10410-10415

  21. Treatment Implications of These New Findings from Neuroimaging and Functional Studies FMS patients were losing 10.5 cm3 of GM annually since the year of their diagnosis a p< 0.001 10 Fibromyalgia patients compared with 10 healthy controls volume (mm3) p< 0.001 p< 0.001 Fibromyalgia patients had significantly lesser gray matter volume in posterior cingulate, insular cortex, MFC and parahippocampalgyrus. Rate of age related decline was significantly greater in fibromyalgia patients than healthy controls (p<0.001) Kuchinad et al, J Neurosci2007;27(15):4004-4007

  22. Fibromyalgia: Brain Volume Changes when Co-morbid with Depression or Anxiety FM – AD = 29 FM + AD = 29 HC = 29 R = - .47 p <.002 GMV – Gray Matter Volume; TIV = Total Intracranial Volume; STPI = State-Trait Personality Inventory AD = Affective Disorder Hsu MC, et.alPain..2009.Jun;143(3):262-267

  23. Fibromyalgia & Anxiety: A Deeper Examination Focus on 1. Hypothalamic pituitary axis 2. Inflammatory cytokines 3. Autonomic nervous system

  24. Neuroendocrine and NeuroimmuneDysregulation in Pain Syndromes Red = inhibitory pathway Green = stimulatory pathway 1Raison CL et al. Trends Immunol 2006;27:24-31; 2Nestler EJ et al. Neuron 2002;34:13-25; 3Blackburn-Munro G et al. J Neuroendocrinol 2001;13:1009-23

  25. Pain is a Mind-Body Disorder: Anxiety/Depression/Insomnia is a Mind-Body Disorder Jain R, et al, Diabetes Report Curr Diab Rep 2011;11:275–284

  26. Autonomic Dysregulation May Augment Pain Norepinephrine-evoked pain 100 10 94.3 P<.05 9 80.0 P<.05 8 80 7 6 P =NS 60 5 54.3 54.3 56.3% P≤0.05 Patients (%) Visual analog scale (norepinephrine-placebo) 4 3 40 P =NS 30.0 30.0 2 1 20 0 11.9% -1 11.9% 16/20 6/20 6/20 0 -2 FM RA HC FM RA HC n=20 n=20 n=20 n=20 n=20 n=20 Martinez-Lavin M et al. BMC MusculoskeletDisord 2002;3:2

  27. Immunologic Impact of Pain With Increasing Duration of Pain Catecholamines, Neurokinin K Increased sympathetic activity Substance P IL-6 Sympathetic mediated pain IL-8 IL-IRa Hyperalgesia, fatigue, depression Serum IL-8 Serum IL-Ra Serum IL-6 * 764.9 *P<0.05 556.25 pg/mL * 37.08 18.45 7.1 • IL-8 is a proinflammatory cytokine, and mediates sympathetic pain • IL-Ra is involved with stress • IL-6 is involved with stress, fatigue, hyperalgesia, depression, and it activates sympathetic pain 7.3 <2-yr symptoms n=23 >2-yr symptoms 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. Potential Clinical Consequences of Relationship of Pain To HPA, Pro-inflammatory Cytokines, and the Autonomic System Potential consequencesof such dysregulation Fatigue Sleep impairment Depressed mood and anhedonia Difficulty concentrating Anxiety and irritability Appetite and libido disturbances Pain Autonomic Nervous System Cytokines Kim YKet al. Prog Neuropsychopharmacol Biol Psychiatry2007;31:1044-53 Raison CL et al. CNS Drugs 2005;19:105-23. Dantzer R. NeurolClin 2006;24:441-60

  29. Patients with Peripheral Neuropathic Pain Experience Significant Comorbid Symptoms Adapted from: Meyer-Rosberg et al. Eur J Pain 2001;5:379-89

  30. Sleep Pathways are Intimately Involved with Multiple Neurotransmitters Thalamus PeF VLPO (GABA, Ga) vPAG (DA) TMN (H) LDT (ACh) Raphe (5-HT) PPT (ACh) SCN LC(NA) Hypothalamus Pons Cerebellum Medulla Complex interactions among the nuclei in the hypothalamus and brainstem determine the onset of sleep Brainstem PeF=perifornicalregion VLPO=ventrolateralpreoptic nucleus. SCN= Supra Chiasmatic Nuclei Saper CB, et al. Nature. 2005;437(7063):1257-1263

  31. Some Brain Regions Do Not “Switch Off” in Insomnia Patients Arousal systems in insomnia patients that do not deactivate from waking to sleep ARAS Thalamus Hypothalamus ARAS Mesial temporal cortex Cingulate cortex Insular cortex ARAS Mesial temporal cortex Hypothalamus ARAS=ascending reticular activating system. Nofzinger EA et al.Am J Psychiatry. 2004;161:2126-2129

  32. PFC Th ARAS Daytime Fatigue in Insomnia Patients Is Related to Relative Hypo-metabolism in Frontal Areas Insomnia patients have lower metabolism during waking in prefrontal cortex, ARAS, and thalamus, compared with healthy controls PFC=prefrontal cortex; Th=thalamus; ARAS=ascending reticular activating system Nofzinger EA et al.Am J Psychiatry. 2004;161:2126-2129

  33. Decreased Hippocampal volume in Insomnia is associated with Cognitive Impairment and Hyper-arousal 4500 Right hippocampus Left hippocampus 4500 Right hippocampus Left hippocampus Hippocampal volume (mm3 ) Hippocampal volume (mm3 ) n=20 4000 4000 3500 3500 3000 3000 2500 2500 2000 2000 0 510152025 0 10203040 A B Duration of insomnia (year) Arousal index (/hr) Higher values on the arousal index correspond to poor sleep quality. Left or right hippocampal volume was negatively correlated with the insomnia duration (left: r=-0.872, p<0.001; right: r=-0.868, p<0.001) (A) and with the arousal index in nighttime polysomnography (left: r=-0.435, p=0.045; right: r=-0.409, p=0.026) (B). Noh et al, 2012, J Clin Neurol ; 8:130-138

  34. “Divided No More” - Insomnia: Emotional and Cognitive Sequelae Insomnia significantly impacts mood and activities of daily living Insomniacs (%) N=570 individuals >18 years, reporting insomnia in the past 12 months. Leger D, et al. Curr Med Res Opin. 2005;21(11):1785-1792

  35. Recommendations from the British Pain Society Excerpts 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 Programmesfor Adults, Consensus Statement, April 2007

  36. A Suggested Clinical Pathway to Managing Anxiety/Depression / Insomnia in a Patient with Pain Routinely screen for Anxiety/ Depression/Sleep Problems Optimize treatment of Pain Use scales/ screeners Non-pharmacological treatment/s If any of 3 still persists Pharmacological treatment/s

  37. GAD-7 and PHQ-9 – Two (mostly) Undiscovered Gems Generalised Anxiety Disorder 7-Item Scale (GAD-7)1 Patient Health Questionnaire (PHQ-9)2 1 Spitzer RL et al. Arch Intern Med 2006;166:1092-1097 2 KroenkeK et al. J Gen Intern Med2001;16:606-613

  38. Recommended Screening Tools for Anxiety and Depression Adapted from: Jain R et al. Curr Diab Rep 2011;11:275-284

  39. And Furthermore...The SEC Model Integrates Non- Pharmacological and Pharmacological RxOf Pain Non-pharmacological Pharmacological Emotional Non-pharmacological Non-pharmacological Sensory Cognitive Pharmacological Pharmacological SEC = Sensory, Emotional, Cognitive

  40. So, what do we do now? • Adopt a model for chronic pain that incorporates the emerging neurobiology and epidemiology of overlap with anxiety / depression1 • Specific interventions we can offer – • CBT1 • Meditation2 • Physical Exercise3 • Medication1 All four have demonstrated + studies in Anxiety /Depression All four have demonstrated + studies in Chronic Pain 1Asmundson GJG, et al. Depress Anxiety 2009:26;888–901; 2Rosenzweig S, et al. J Psychosom Res 2010;68:29-36; 3 Hoffman MD et al. Curr Pain Headache Rep 2007;11:93-97

  41. Cognitive Behavioral Management of Chronic Pain p=0.032 p=0.021 • Six weekly 90-minute group sessions • Based on CBT attention management manual Pre-treatment Post-treatment 3-month follow up 6-month follow up Average pain (0-10 scale) n=18 Pain-related anxiety(PASS-20) n=20 (n=31; data for individuals completing 6-month follow-up) Adapted from: Elomaa MM et al. Eur J Pain 2009;13(10):1062-1067

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

  43. 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 N=12 Before treatment After treatment 69 Salivary cortisol concentration 64.1 63.1 9 8 7 6 5 4 3 2 * 57.3 *p<0.05 48.9 * Pre-treatmentPost-treatment 38 ng/ml 24.9 * 22.4 13.5 13.3 13.3 * 5.5 0800 1000 1200 1400 1600 1800 2000 2200 Positive VAS % of Pain CES-D Tender Score Area Score Time of sample Points HPA=hypothalamic-pituitary-adrenal; CBT=cognitive behavioral therapy; CES-D=Center for Epidemologic Studies Depression Rating Scale Adapted from: Bonifazi M et al. Psychoneuroendocrinology2006;31:1076-86

  44. Fitness & Hippocampal Volume – Further Reason to bring Exercise into our Rx Plan Scatterplots showing increase in fitness (VO2 peak) is related to increase in hippocampal volume (cm3) Correlations significant for both left and right (even after including age, sex, years of education as covariates) Erickson KI, et al. Hippocampus. 2009; ahead of publication.

  45. The Results of 10 Weeks of Physical Exercise in DPN Intra-epidermal Nerve Fiber Branching (+0.11±0.15 branch nodes/fiber, P=.008) Neuropathic Symptom Scores (Michigan Neuropathy Screening Instrument) (−1.24±1.8 on MNSI, P=.01) 1 = pre-intervention measures, 2 = post-intervention measures Kluding PM et al. J Diabetes Complications 2012; June 18 [epub ahead of publication]

  46. Pharmacological Treatment Options for Anxiety Disorders

  47. Mixed Pain (e.g. Back Pain) Reduces Cortical Thickness Seminowitz DA, et al. J Neurosci2011;31(20):7540-7550

  48. Good News – Yes! Improved Structural & Cognitive Functioning Post Treatment Seminowitz DA, et al. J Neurosci2011;31(20):7540-7550

  49. Layering of Therapeutic Options

  50. In Conclusion ~ 1of 3: Amazing Similarity Between Mind and Body – We are Truly United ‘Physical’ Pain ‘Emotional’ Pain Tracey I, et al. Cell2012;148(6):1308-1308e2

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