1

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

Rakesh Jain, MD, MPH

R/D Clinical Research, Inc.Lake Jackson, Texas, USATexas Tech Health Sciences Center – Permian BasinMidland, Texas, USA

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

Lifetime Prevalence of Mental Illnesses is High

14.6%

20.8%24.8%

28.8%

0%

10%

20%

30%

40%

50%

Substance UseD/O

Mood D/O Impulse ControlD/O

Anxiety D/O

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

Is Pain Impacted by the Co-occurrence of Psychiatric Disorders?

Pain Severity Pain Interference0

1

2

3

4

5

6

7

8

Pain only Pain and Anxiety Pain and Depression Pain, Depression and Anxiety

Bri

ef P

ain

In

ven

tory

Pai

n S

core

(m

ean

)ra

ng

e:

0-1

0

**

*

*

**

*P<0.001

Bair MJ, et al. Psychosom Med. 2008;70:890-897. 5

6

Pain Condition (Headaches) and Depression/Anxiety

Major De-pression

Panic D/O Generalized Anxiety D/O

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

1.0 1.0 1.0

2.84

3.293.03

n=15,330 - without HAs n= 3,045 - with headaches

Adj

uste

d od

ds ra

tio

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

*

**

“Ring of Fire”: Odds Ratio of Psychiatric Comorbidities in Fibromyalgia

Fibromyalgia

Any Anxiety Disorder

6.7

Eating Disorder

2.4

Substance Use Disorder

3.3

Major Depression

2.7

Arnold LM, et al. J Clin Psychiatry. 2006;67:1219-1225. 7

6.1

7.9

10.3

6.7

8.9

11.0

Mild Moderate Severe

HADS - depression score

HADS - anxiety score

BPI – DPN Average Pain Severity

Mea

n s

core

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

2.0

4.6*

3.1

5.4*

No Painn=50

Chronic Painn=40

Me

an

sc

ore

HADS-depression score

HADS-anxiety score

(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

5.95

7.92

10.16

0

2

4

6

8

10

12

NPAD-d in lowestquartile

NPAD-d in middlequartiles

NPAD-d in highestquartile

HA

DS

An

xiet

y S

ub

-sca

le M

ean

S

core

s (

s sc

ore

ran

ge

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

Do Anxiety, Depression, or Sleep Problems Predict the Development of Pain?

15 month prospective study, 3171 followed, 324 developed chronic widespread pain

score 0 - 4 score 5 - 7 score 8 -21

11.4

2.6

Anxiety (HAD Anxiety sub-score)

Od

ds

Ra

tio

score 0 - 2 score 3 - 5 score 6 -20

1

1.8

2.9

Depression (HAD Depression sub-score)

Od

ds

Rati

o

score 0 - 3 score 4 - 8 score 9 -20

1

2

3.4

Sleep (Sleep Problem Scale)

Od

ds

Rati

o

Gupta A, et al. Rheumatology. 2007;46:666-671. 11

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?

The Pain Circuit Involves Sensory, Emotional, and Cognitive Regions of the Brain

Fast, myelinate

d A-fibers

Slow, unmyelinated C-fibers

Somatosensory cortex

Thalamus

Limbic system

CerebrumBrainstem

Spinal cordSpinothalamic tract

Dorsalganglion

Afferent nerve fiber

Adapted from Giordano J. Pain Physician. 2005;8:277-290. 14

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 RegionsPrimary sensory and motor corticesThalamusPosterior insula

Emotional/Affective RegionsAnterior cingulate AccumbensPosterior cingulate Hippocampus Orbitofrontal cortex ThalamusMedial prefrontal cortex AmygdalaAnterior insula Caudate

Cognitive/Integrative RegionsPrefrontal cortexTemporal lobeParietal cortex

Modulatory RegionsMidbrain (PAG, NCu) Cortical regionsPaphe nucleus Subcortical regions

Regi

onal

Inte

racti

ons

Borsook D, et al. Neuroscientist. 2010;16(2):171-185. 15

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

Negative Emotions Robustly Increased Pain and Autonomic Response

Change in Emotion (Emotion-Baseline)

Cha

nge

in P

ain/

Unp

leas

antn

ess

(Em

otio

n B

asel

ine)

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.Rainville P, et al. Pain 2005;118:306-318. 17

CORTICO-LIMBIC INPUT

PAGOPIOIDS

RMCNE

DLF

NRM5-HT

SPINAL INTER-

NEURON

MIDBRAINBRAINSTREAM

Primary nociceptive

afferents

(+)

(+)

(-)

(+)

(+)

(+)

(-)(-)

(-)

PSTT

GABAINTER-

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

Pain and Depression: a Deeper Examination

• Focus on:– HPA– Inflammatory cytokines – Autonomic nervous system

HPA=hypothalamic-pituitary axis. 19

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

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

Autonomic Dysregulation May Augment Pain

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

(nor

epin

eph

rine-

pla

cebo

)

0

20

40

60

80

100

30.0 30.0

Pa

tie

nts

(%

)

n=20

n=20 n=20

P≤0.05

P=NS

16/20 6/20 6/20

56.3%

94.3%

54.3%

11.9%

54.3%

11.9%

Vis

ual a

nalo

g s

cale

Martinez-Lavin M, et al. BMC Musculoskelet Disord. 2002;3:2. 22

A Comprehensive, Neurobiological View of Pain and Psychology

Jain R, et al. Curr Diab Rep. 2011;11:275-284. 23

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

Pain

AutonomicNervous System

Cytokines

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

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 …

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

<2-yr symptoms >2-yr symptoms0

75

150

225

300

375

450

525

600

675

750

Serum IL-8 Serum IL-Ra Serum IL-6

pg

/mL

n=23 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

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

GM Loss in Pain – in Regions Also Involved With Anxiety Regulation

0

400,000

800,000

1,200,000

1,600,000

GM WM CSF Total Volume

HC FM

*P <0.001

Vo

lum

e (m

m3 )

• 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. 29

FM – AD = 29 FM + AD = 29

HC = 29

R = –0.47P<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 InventoryHsu MC, et al. Pain. 2009;143(3):262-267. 30

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

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?

First: We use Neurobiology to Understand our Treatment Options

Tracey I, Dickenson T. Cell. 2012;148:1308-1308, e2 . 34

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

7.1

41.2

6.1*

38.2*

5.6*

31.9*

5.7*

34.9*

Average Pain (0-10 scale) n=18 Pain-related Anxiety (Pass-20)n=20

Pre-treatment

Post-treatment

3 month Follow-up

6 month Follow-up

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

0.37

0.91

-0.88

-1.50

-0.64

-1.21

Depression Anxiety Pain Interference

Worsening

Improvement

Comparison group n=37

Intervention group n=41

Change from Baseline Scores

CES-D STAI BPI-Interference

Mind-Body Intervention for Older Adults with Chronic Pain

Berman RLH, et al. J Pain. 2009;10(1):68-79. 37

Long-term Benefits of Psychotherapy in FM (12-Month Follow-up Data)

% of Patients Reporting -60 -40 -20 0 20 40 60

AttentionPlacebo (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

• 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

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

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

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

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”

Pain (13/664)

Fatigue (4/200)

Sleep (4/141)

Depressed mood (12/631)

-0.24(P=0.10)

0.05(P=0.71)

-0.15(P=0.50)

-0.24(P=0.004)

Outcome (# Study Arms/# Patients)

Effect Size

Bernardy K, et al. J Rheumatol. 2010;37(10):1991-1205. 43

Tai Chi in Chronic Pain: Demonstrated Effectiveness of a Mind-Body Intervention

Tai Chi group, n=33Control 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

• 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

Pharmacological Treatment Options forAnxiety and Mood Disorders

• Gabapentin • Pregabalin

• Fluoxetine• Sertraline• Paroxetine• Citalopram• Escitalopram

• Lorazepam• Clonazepam• Alprazolam

Benzos SSRIs

α 2 δ ligandsSNRIs• TCAs (many)

• Venlafaxine• Duloxetine• Desvenlafaxine• milnacipran

46

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

VASScore

(1-100)

% of Pain Area

CES-DScore(0-60)

*

*

*

*

*P<0.05

Positive Tender

Points (n)

47

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

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

Routinely Screen for

Anxiety D/Os

Use Scales/Screeners

Optimize Treatment of

Pain

If Anxiety still persists

Non-pharmacological

treatment(s)

Pharmacological treatment(s)

49

Scales for Diagnosing Anxiety and Depression

HADS PHQ-9

GAD-7

50

A Clinically Useful Anxiety Screener: GAD-7

Kroenke K, et al. Ann Intern Med. 2007;146:317-325. 51

0.92

0.820.78 0.760.76 0.75 0.74 0.75

Generalized AnxietyD/O

PanicD/O

Social Anxiety D/O PTSD

Sensitivity

SpecificityGAD-7 Score of ≥8

GAD-7: Useful in Detecting Multiple Anxiety Disorders

Kroenke K, et al. Ann Intern Med. 2007;146:317-325. 52

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

53

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

PHQ-9

54

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”

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

Total Score Depression Severity

0-4 None

5-9 Mild

10-14 Moderate

15-19 Moderately Severe

20-27 Severe

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:

Optimum would be early, full, and sustained control over ALL symptoms

Pain

Sleep

Fatigue

Cognitive

Metabolic

57

What Are We Treating When We “Treat” a Patient ?

Cognitive disturbanceFatigue

Sleep disturbance

PainMetabolic syndrome

58

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

SolutionProblem

59

Target Symptoms and Shared Neurobiology of Chronic Pain and Depression

Genetic predisposition

Neuroendocrine- immune

dysfunction

CSS

ANS dysfunctionPoor sleep

Trauma Psychological factors, stress

Infections, Inflammation

Neonatal, Childhood trauma

Otherfactors

Hyperexcitement of central neurons Environmental,

ChemicalCentral

sensitization

Central sensitization

Other mechanisms

Yunus MB. Semin Arthritis Rheum. 2007;36:339-356. 60

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