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“ Divided No More” Neurobiologic Mind-Body Unification of Depression/ Anxiety/ Insomnia & Chronic Pain. Rakesh Jain, USA. - PowerPoint PPT Presentation
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“Divided No More”
Neurobiologic Mind-Body Unification of Depression/ Anxiety/ Insomnia
& Chronic Pain
Rakesh Jain, USA
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.
0%
10%
20%
30%
40%
50%
Substance UseDisorder
Mood Disorder Impulse-ControlDisorder
Anxiety Disorder
24.8%28.8%
14.6%
20.8%
Anxiety & Depressive D/Os are Very Common Clusters of Psychiatric Disorders
Kessler RC et al. Arch Gen Psychiatry. 2005;62:593-602.
N = 9,282Risk of any disorder 46.4 %
2 or more disorders 27.7 %
3 or more disorders 17.3 %
Kalaydjian AK et al. Psychosom Med 2008;70:773-80
Major De-pression
Panic D/O Generalized Anxiety D/O
1.0 1.0 1.0
2.84
3.293.03
n=15,330 - without headachesn= 3,045 - with headaches
Ad
just
ed o
dd
s ra
tio
Pain Condition (Headaches) and Anxiety Disorders
Adjusted odds ratio (adjusted for age, race, sex & educational status)
Weighted 12-month adjusted odds ratio of association between severe headaches or migraine with mental
disorders
* **
p<0.05*
Blozik E et al. BMC Musculoskel Dis 2009;10:13
NPAD-d in lowest quartile
NPAD-d in middle quartiles
NPAD-d in highest quartile
0
2
4
6
8
10
12
5.95
*
7.92
*
10.16
HA
DS
An
xiet
y S
ub
-sca
le M
ean
Sco
res
(s s
core
ran
ge
0-21
)
N=448
* p<0.001
HADS – Hospital Anxiety and Depression ScaleNPAD-d – Neck Pain and Disability Scale German Version
Neck Pain & Anxiety – Increasing Pain Predicts Increasing Anxiety
“Ring of Fire”: Odds Ratio of Psychiatric Comorbidities in FM
Arnold LM et al. J Clin Psychiatry 2006;67:1219-25
FibromyalgiaAny
Anxiety Disorder
6.7
Any Anxiety Disorder
6.7
Eating Disorder
2.4
Eating Disorder
2.4
Substance Use Disorder
3.3
Substance Use Disorder
3.3
Major Depressio
n2.7
Major Depressio
n2.7
N = 108 with fibromyalgia, 228 without fibromyalgia
Gore M et al. J Pain Symptom Manage 2005;30(4):374-85
Mild Moderate Severe
6.1
7.9
10.3
6.7
8.9
11.0
HADS-depression score
HADS-anxiety score
*
DPNP Patients – Relationship Between Pain & Mental Disorders
BPI – DPN Average Pain Severity
Sco
re
** *
HADS = Hospital Anxiety and Depression ScaleBPI = Brief Pain Inventory
N = 255
Is Pain Affected by the Co-occurrence of Anxiety and/or Depression ?
Bair MJ et.al. Psychosom Med 2008;70:890-897
Bri
ef P
ain
In
ven
tory
Pai
n S
core
(m
ean
) ra
ng
e :
0-10
Pain + Depression (n=98)
1
2
4
6
5
3
8
7
Pain Severity Pain Interference
Pain only (n=271)
Pain + Anxiety (n=15)
Pain + Anxiety + Depression (n=116)
*p<0 .001
**
* *
**
Jenewein J et al. J Psychosom Res 2009;66:119-26
No Pain n=50
Chronic Pain
n=40
2.0
*4.6
3.1
*5.4HADS-depression score
HADS-anxiety score
Mea
n
sco
reChronic 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
*
*
Do Anxiety, Depression, or Sleep Problems Predict the Development of Pain?
11.4
2.6
score 0-4 score 5-7 score 8-21
Gupta A et al. Rheumatology 2007;46:666-71
1
1.8
2.9
score 0-2 score 3-5 score 6-20
Anxiety (HADS Anxiety sub-score) Depression (HADS Depression sub-score)
Sleep (Sleep Problem Scale)
15-month prospective study, 3171 followed, 324 developed chronic widespread pain
Odds
ratio
Odds ratio
Odds
ratio
Negative Emotions Robustly Increased Pain and Autonomic Response
Rainville P et al. Pain 2005;118:306-318
Change in Emotion (Emotion Baseline)
Change in
Pain
/Unple
asa
ntn
ess
(Em
oti
on B
ase
line)
RelaxationSadnessAngerFear and AnxietyReliefSatisfaction
-50.0
50.0
100.0
-100.0
-20.0 -10.0
20.010.0
R2=0.57
(Emotions hypnotically induced)N=26
Anxiety Severity and its Relationship to Pain
Celiker R et al. Clin Rheumatol 1997;16:179-84
Pain severity related to state anxiety (r=.2706, P>0.05) and trait anxiety (r=.3328, P<0.05) inventory scores
State anxiety
Trait anxiety
20 30 40 50 60 700
2
4
6
8
10
VA
S(V
isu
al A
nalo
g S
cale
)
The Pain Circuit Involves Sensory, Emotional, and Cognitive Regions of the Brain
Adapted from Giordano J. Pain Physician 2005;8:277-90
Slow, unmyelinated C-fibers
Somatosensory cortex
Thalamus
Limbic system
CerebrumBrainstem
Spinal cordSpinothalamic tract
Dorsalganglion
Afferent nerve fiber
Fast, myelinated
A-fibers
Shared Anatomy: Complex Circuits Involve Sensory, Cognitive, and Emotional Regions
Apkarian AV et al. Eur J Pain 2005;9:463-84
Pain and Anxiety/ Depression have a Strongly Shared Neuroanatomy
ACC
Insula
Thal
PFC
VS
Hippo
AMG OFC
Hyp
Dorsal root ganglion
PAG PB
Pain
S1 S2
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
The “Pain Matrix”: The Reason Why So Many Pain Patients have Multiple Symptoms
Borsook D et al. Neuroscientist 2010;16(2):171-85
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 RegionsPrimary sensory and motor corticesThalamusPosterior insula
Emotional/Affective Regions
Cognitive/Integrative RegionsPrefrontal cortexTemporal lobeParietal cortex
Modulatory RegionsReg
iona
l Int
erac
tions
Anterior cingulatePosterior cingulateOrbitofrontal cortex
Medial prefrontal cortex Anterior insula
AccumbensHippocampus
ThalamusAmygdalaCaudate
Midbrain (PAG, Ncu)Paphe nucleus
Cortical regionsSubcortical regions
In Pain Patients - Brain Perfusion Studies Implicate Anxiety Regulatory Centers
Guedj E et al. J Nucl Med 2008;49;11:1798-1803
Bilateral parietal perfusion (BA7) Bilateral post-central perfusion (BA4) Left anterior temporal perfusion
Positive correlation Negative correlation
Giordano J. Pain Physician 2005;8:277-290
CORTICO-LIMBIC INPUT
PAGOPIOIDS
RMCNE
DLF
NRM5-HT
SPINAL INTER-
NEURON
MIDBRAINBRAINSTREAM
Primary nociceptiv
e afferents
(+)
(+)
(-)
(+)
(+)
(+)
(+)
(-)(-)
(-)
PSTT
GABAINTER-
NEURON
Many Neurotransmitters Are Shared by Pain & Anxiety
5-HT=5-hydroxytryptamine; DLF=dorolateral funiculus; NRM=nucleus raphe mangus; RMC=magnocellular nuclei; PAG=periaqueductal grey substance; PSTT=paleospinothalic tract.
Back Pain: Gray Matter Atrophy in Areas Involved with Cognition and Emotional Regulation
Apkarian AV et.al. J Neurosci 2004;24(46):10410-10415
Patients with chronic back pain (CBP) had 5-11% less whole brain gray matter, equivalent to 10-20 years of normal aging
volume (mm3)
a
Treatment Implications of These New Findings from Neuroimaging and Functional Studies
Fibromyalgia patients had significantly lesser gray matter volume in posterior cingulate, insular cortex, MFC and parahippocampal gyrus. Rate of age related decline was significantly greater in fibromyalgia patients than healthy controls (p<0.001)
10 Fibromyalgia patients compared with 10 healthy controls
Kuchinad et al, J Neurosci 2007;27(15):4004-4007
p< 0.001
p< 0.001
p< 0.001
FMS patients were losing 10.5 cm3 of GM annually since the year of their diagnosis
Fibromyalgia: Brain Volume Changes when Co-morbid with Depression or Anxiety
GMV – Gray Matter Volume; TIV = Total Intracranial Volume; STPI = State-Trait Personality Inventory
FM – AD = 29 FM + AD = 29
HC = 29
Hsu MC, et.al Pain..2009.Jun;143(3):262-267
R = - .47p <.002
AD = Affective Disorder
Fibromyalgia & Anxiety: A Deeper Examination
• Focus on
1. Hypothalamic pituitary axis
2. Inflammatory cytokines
3. Autonomic nervous system
Neuroendocrine and Neuroimmune Dysregulation in Pain Syndromes
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 et al. J Neuroendocrinol 2001;13:1009-23
Red = inhibitory pathway
Green = stimulatory pathway
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
Autonomic Dysregulation May Augment Pain
Martinez-Lavin M et al. BMC Musculoskelet Disord 2002;3:2
n=20 n=20n=20
P <.05
P <.05
P =NS
n=20 n=20n=20
Norepinephrine-evoked pain
-2
-1
0
1
2
3
4
5
6
7
8
9
10
FM RA HC
Vis
ual
an
alo
g s
cal
e
(no
rep
inep
hri
ne-
pla
ceb
o)
Pat
ien
ts (
%)
80.0
30.0 30.0
0
20
40
60
80
100
FM RA HC
56.3%
16/20 6/20 6/20
P=NS
94.3
54.354.3
11.9% 11.9%
P≤0.05
<2-yr symptomsn=23
>2-yr symptomsn=23
18.45 7.1
556.25
37.087.3
764.9
Serum IL-8 Serum IL-Ra Serum IL-6
*P<0.05
Immunologic Impact of Pain With Increasing Duration of Pain
Wallace DJ et al. Rheumatology 2001:40:743-749 Schwartz YA et al. Am J Resp Cell Mol Biol 1999;21:388-394
• 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
Substance P Increased sympathetic activity
Hyperalgesia, fatigue, depression
Sympathetic mediated pain
IL-6
IL-8
IL-IRa
Catecholamines, Neurokinin K
pg
/m
L
Patients met ACR criteria for FM.
*
*
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
Kim YK et al. Prog Neuropsychopharmacol Biol Psychiatry 2007;31:1044-53 Raison CL et al. CNS Drugs 2005;19:105-23. Dantzer R. Neurol Clin 2006;24:441-60
Pain
Autonomic
Nervous System
Cytokines
0 10 20 30 40 50 60 70
Poor appetite
Anxiety
Depression
Concentration difficulties
Drowsiness
Lack of energy
Difficulty sleeping
% patients with moderate to very severe discomfort (n=126)
Adapted from: Meyer-Rosberg et al. Eur J Pain 2001;5:379-89
Patients with Peripheral Neuropathic Pain Experience Significant Comorbid Symptoms
Sleep Pathways are Intimately Involved with Multiple Neurotransmitters
Complex interactions among the nuclei in
the hypothalamus and brainstem determine the onset of sleep
Saper CB, et al. Nature. 2005;437(7063):1257-1263
Thalamus
PeF
vPAG (DA)VLPO (GABA, Ga)
TMN (H)Raphe (5-HT)
PPT (ACh)
LDT (ACh)
LC(NA)SCN
Brainstem
CerebellumMedulla
HypothalamusPons
PeF=perifornical regionVLPO=ventrolateral preoptic nucleus.SCN= Supra Chiasmatic Nuclei
Nofzinger EA et al. Am J Psychiatry. 2004;161:2126-2129
ARAS
Thalamus
Mesial temporal cortex
Insular cortex
ARAS
Mesial temporal cortex
Hypothalamus
Cingulate cortex
Hypothalamus
Arousal systems in insomnia patients that do not deactivate from waking to sleep
ARAS
ARAS=ascending reticular activating system.
Some Brain Regions Do Not “Switch Off” in Insomnia Patients
Insomnia patients have lower metabolism during waking in prefrontal cortex, ARAS, and thalamus, compared with healthy controls
Nofzinger EA et al. Am J Psychiatry. 2004;161:2126-2129
PFC
Th
ARAS
PFC=prefrontal cortex; Th=thalamus; ARAS=ascending reticular activating system
Daytime Fatigue in Insomnia Patients Is Related to Relative Hypo-metabolism in Frontal Areas
Decreased Hippocampal volume in Insomnia is associated with Cognitive Impairment and Hyper-arousal
0 5 10 15 20 25
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
4500 Right
hippocampus Left
hippocampus 4000
Hip
pocam
pal volu
me (
mm
3 )
3500
3000
2500
2000 0 10 20 30
40 B Arousal index
(/hr)
4500 Right hippocampus Left hippocampus
4000
Hip
pocam
pal volu
me (
mm
3 )
3500
3000
2500
2000
A Duration of insomnia (year)
n=20
“Divided No More” - Insomnia: Emotional and Cognitive Sequelae
Leger D, et al. Curr Med Res Opin. 2005;21(11):1785-1792
Insomniacs (%)
Insomnia significantly impacts mood and activities of daily living
N=570 individuals >18 years, reporting insomnia in the past 12 months.
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 Programmes for Adults, Consensus Statement, April 2007
A Suggested Clinical Pathway to Managing Anxiety/Depression / Insomnia in a Patient with Pain
Routinely screen for Anxiety/
Depression/SleepProblems
Use scales/screeners
Optimize treatment of
Pain
Pharmacological treatment/s
Non-pharmacological
treatment/s
If any of 3 still persists
GAD-7 and PHQ-9 – Two (mostly) Undiscovered Gems
1 Spitzer RL et al. Arch Intern Med 2006;166:1092-1097 2 Kroenke K et al. J Gen Intern Med 2001;16:606-613
Generalised Anxiety Disorder 7-Item Scale (GAD-7)1
Patient Health Questionnaire (PHQ-9)2
Recommended Screening Tools for Anxiety and Depression
Adapted from: Jain R et al. Curr Diab Rep 2011;11:275-284
Scale Used to assess Scoring
GAD-7(Generalised Anxiety Disorder-7)
[patient rated]
Generalized anxiety disorder Total score range 0-21Cut points:
• 5 (mild)• 10 (moderate)• 15 (severe)
PHQ-9(Physical Health Questionnaire-9)
[patient rated]
Depression- Sensitive to changes in
symptom severity following intervention
Total score range 0-27Cut points:
• 5 (mild)• 10 (moderate)• 15 (moderately severe)• 20 (severe)
HADS(Hospital Anxiety and Depression Scale)
[patient rated]
Anxiety and depression • 0-7 (none)• 8-10 (borderline)• ≥11 (definite)
And Furthermore...The SEC Model Integrates Non- Pharmacological and Pharmacological Rx Of Pain
SensoryCognitive
Emotional
Non-pharmacological
Non-pharmacological
Non-pharmacological
Pharmacological
Pharmacological PharmacologicalSEC = Sensory, Emotional, Cognitive
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
1 Asmundson GJG, et al. Depress Anxiety 2009:26;888–901; 2 Rosenzweig S, et al. J Psychosom Res 2010;68:29-36; 3 Hoffman MD et al. Curr Pain Headache Rep 2007;11:93-97
Adapted from: Elomaa MM et al. Eur J Pain 2009;13(10):1062-1067
Cognitive Behavioral Management of Chronic Pain
(n=31; data for individuals completing 6-month follow-up)
• Six weekly 90-minute group sessions
• Based on CBT attention management manual
Average pain (0-10 scale) n=18
Pain-related anxiety(PASS-20) n=20
Series10
1
2
3
4
5
6
7
87.1
6.15.6 5.7
Series10
5
10
15
20
25
30
35
40
4541.2
38.2
31.934.9
p=0.032 p=0.021
3-month follow up
6-month follow up
Pre-treatment
Post-treatment
Depression Anxiety Pain Interference
0.37
0.91
-0.88
-1.5
-0.64
-1.21
Comparison group n=37
Intervention group n=41worseningimprovement
Mind-Body Intervention for Older Adults with Chronic Pain
Berman RLH et al. J Pain 2009;10(1):68-79
Change from Baseline Scores
CES-D STAI BPI - Interference
3 weeks of multidisciplinary treatment consisted of education, stretching, CBT, relaxation training and aerobic exercise
Adapted from: Bonifazi M et al. Psychoneuroendocrinology 2006;31:1076-86
Multidisciplinary Treatment: Impact on Improvement and HPA Changes
HPA=hypothalamic-pituitary-adrenal; CBT=cognitive behavioral therapy; CES-D=Center for Epidemologic Studies Depression Rating Scale
Before admission and treatmentBefore treatment After treatment
TenderPoints
Score Area Score
64.1
57.3
22.4
5.5
48.9
38
13.3
63.1
24.9
69
13.5
13.3
Positive VAS % of Pain CES-D
*
*
*
*
*p<0.05
N=12
Salivary cortisol concentration
Pre-treatmentPost-treatment
9
8
7
6
5
4
3
2
0800 1000 1200 1400 1600 1800 2000 2200
Time of sample
ng
/ml
Fitness & Hippocampal Volume – Further Reason to bring Exercise into our Rx Plan
Erickson KI, et al. Hippocampus. 2009; ahead of publication.
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)
The Results of 10 Weeks of Physical Exercise in DPN
Neuropathic Symptom Scores (Michigan Neuropathy Screening Instrument)
(−1.24±1.8 on MNSI, P=.01)
Intra-epidermal Nerve Fiber Branching(+0.11±0.15 branch nodes/fiber, P=.008)
Kluding PM et al. J Diabetes Complications 2012; June 18 [epub ahead of publication]
1 = pre-intervention measures, 2 = post-intervention measures
Mixed Pain (e.g. Back Pain) Reduces Cortical Thickness
Seminowitz DA, et al. J Neurosci 2011;31(20):7540-7550
Good News – Yes! Improved Structural & Cognitive Functioning Post Treatment
Seminowitz DA, et al. J Neurosci 2011;31(20):7540-7550
In Conclusion ~ 1of 3: Amazing Similarity Between Mind and Body – We are Truly United
Tracey I, et al. Cell 2012;148(6):1308-1308e2
‘Emotional’ Pain
‘Physical’ Pain
In Conclusion ~ 2of 3: Treatment Implications of “Divided No More”
Tracey I, et al. Cell 2012;148(6):1308-1308e2
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