Rakesh Jain, USA

“Divided No More”

Neurobiologic Mind-Body Unification of Depression/ Anxiety/ Insomnia

& Chronic Pain

Rakesh Jain, USA

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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

Brain Areas Involved in Pain Processing – “Divided No More”

Borsook D, et al. Mol Pain 2007;3:25.

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

Pharmacological Treatment Options for Anxiety Disorders

Benzodi-azepines SSRIs

α2δ ligandsSNRIs

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

Layering of Therapeutic Options

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

In Conclusion ~ 3 of 3: Redefining Optimum Response to Treatment

Optimum would be early, full, and sustained control over ALL symptoms, regardless of our specialty!

Pain

Sleep

Fatigue

Anxiety

Mood