Pain and Depression

Report
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
1
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
1. Is there a link between Chronic Pain
and Depression
3
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 %
50%
40%
28.8%
30%
24.8%
20.8%
20%
14.6%
10%
0%
Substance Use
D/O
Kessler RC, et al. Arch Gen Psychiatry. 2005;62:593-602.
Mood D/O
Impulse Control
D/O
Anxiety D/O
4
Is Pain Impacted by the Co-occurrence
of Psychiatric Disorders?
8
*P<0.001
*
6
*
*
5
range: 0-10
Pain Score (mean)
*
*
7
Brief Pain Inventory
*
4
3
2
1
0
Pain Severity
Pain only
Pain and Anxiety
Bair MJ, et al. Psychosom Med. 2008;70:890-897.
Pain Interference
Pain and Depression
Pain, Depression and Anxiety
5
Pain Condition (Headaches)
and Depression/Anxiety
*P<0.05
*
3.5
3.29
*
*
2.84
3.0
Adjusted odds ratio
3.03
2.5
2.0
1.5
1.0
1.0
1.0
1.0
Weighted 12 month
adjusted odds ratio of
association between
severe headaches or
migraine and mental
disorders
0.5
0.0
Major
Depression
Panic D/O
n=15,330 - without HAs
Generalized
Anxiety D/O
n= 3,045 - with headaches
Adjusted odds ratio (adjusted for age, race, sex, and educational status).
Kalaydjain A, Merikangas K. Psychosom Med. 2008;70:773-780.
6
“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
Arnold LM, et al. J Clin Psychiatry. 2006;67:1219-1225.
Major
Depression
2.7
7
DPNP Patients: Relationship Between
Pain and Mental Disorders
*P<0.01
*
HADS - depression score
Mean score
HADS - anxiety score
*
*
10.3
*
11.0
8.9
7.9
6.7
6.1
Mild
Moderate
Severe
BPI – DPN Average Pain Severity
Gore M, et al. J Pain Symptom Manage. 2005;30(4):374-385.
8
Chronic Pain After Accidental Injury and its
Relationship to Depression and Anxiety
(HADS-Depression score)
*P<0.05
5.4*
HADS-depression score
Mean score
HADS-anxiety score
• 3 years later: 45% had
chronic pain
4.6*
• >10% developed
subsyndromal PTSD
3.1
• All but one patient with PTSD
(full or sub-syndromic) had
chronic pain
2.0
No Pain
n=50
Jenewein J, et al. J Psychosom Res. 2009;66:119-126.
• 3 years after accident: 4.4%
developed PTSD
Chronic Pain
n=40
9
HADS Anxiety Sub-scale Mean
Scores
(s score range 0–21)
Dose-Response Curve Exists Between
Chronic Pain and Psychiatric Difficulties
*P<0.001
12
10.16 *
10
7.92 *
8
6
5.95
4
2
0
NPAD-d in lowest
quartile
NPAD-d in middle
quartiles
NPAD-d in highest
quartile
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
2.6
1.4
1
score 0 - 4
score 5 - 7
score 8 -21
Odds Ratio
Anxiety (HAD Anxiety sub-score)
3.4
2
1
score 0 - 3
score 4 - 8
Odds Ratio
Odds Ratio
Do Anxiety, Depression, or Sleep Problems
Predict the Development of Pain?
2.9
1.8
1
score 0 - 2
score 3 - 5
score 6 -20
Depression (HAD Depression subscore)
15 month prospective
study, 3171 followed,
324 developed chronic
widespread pain
score 9 -20
Sleep (Sleep Problem Scale)
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
2. Why is there a link between chronic
pain and depression?
13
The Pain Circuit Involves Sensory, Emotional,
and Cognitive Regions of the Brain
Somatosensory cortex
Limbic system
Cerebrum
Thalamus
Slow,
unmyelinated
C-fibers
Brainstem
Spinal cord
Spinothalamic
tract
Dorsal
ganglion
Fast,
myelinated
A-fibers
Afferent
nerve fiber
Adapted from Giordano J. Pain Physician. 2005;8:277-290.
14
Regional Interactions
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
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.
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
Relaxation
Sadness
Anger
Fear and Anxiety
Relief
Satisfaction
Change in Pain/Unpleasantness
(Emotion Baseline)
Negative Emotions Robustly Increased
Pain and Autonomic Response
100.0
R2=0.57
50.0
10.0
–20.0
20.0
–10.0
–50.0
–100.0
Change in Emotion
(Emotion-Baseline)
(Emotions hypnotically induced)
N=26.
Rainville P, et al. Pain 2005;118:306-318.
17
Many Neurotransmitters are Shared by Pain
and Depression
Primary
nociceptive
afferents
(-) (-)
BRAINSTREAM
PSTT
MIDBRAIN
(+)
(+)
NRM
5-HT
RMC
NE
(+)
(+)
(+)
(-)
SPINAL
INTERNEURON
GABA
INTERNEURON
PAG
OPIOIDS
CORTICOLIMBIC
INPUT
(+)
(-)
DLF
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
Green = stimulatory pathway
Red = inhibitory 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 MindBody (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
Norepinephrine-evoked pain
100
16/20
6/20
6/20
94.3%
10
9
8
60
56.3%
P≤0.05 54.3%
40
54.3%
P=NS
30.0
30.0
20
Visual analog scale
(norepinephrine-placebo)
Patients (%)
80
P <.05
P <.05
7
6
P =NS
5
4
3
2
1
0
11.9%
11.9%
-1
-2
0
Fibromyalgia Rheumatoid
arthritis
n=20
n=20
Martinez-Lavin M, et al. BMC Musculoskelet Disord. 2002;3:2.
Healthy
controls
FM
RA
HC
n=20
n=20
n=20
n=20
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
Pain
• Depressed mood and anhedonia
• Difficulty concentrating
Autonomic
Cytokines
• Anxiety and irritability
Nervous
• Appetite and libido disturbances
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.
24
How Pain and Psychiatric Difficulties Get
Tied Together by Neurobiology
Tracey I, Dickenson T. Cell. 2012;148:1308-1308, e2 .
25
And the consequences of this overlap are …
26
Immunologic Impact of Pain With Increasing
Duration of Pain
*P<0.001
750
*
Catechols, Neurokinin K
675
Increased
sympathetic
activity
Substance P
600
pg/mL
525
IL-6
450
375
IL-8
300
Sympathetic
mediated pain
225
IL-IRa
150
75
*
0
•
<2-yr symptoms
n=23
Serum IL-8
>2-yr symptoms
n=23
Serum IL-Ra
Serum IL-6
•
•
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
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
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.
28
GM Loss in Pain – in Regions Also
Involved With Anxiety Regulation
1,600,000
HC
FM
*
*P<0.001
Volume (mm3)
1,200,000
800,000
*
400,000
0
GM
WM
CSF
Total Volume
• 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
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.
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
3. What do we do about this chronic pain
and depression link?
33
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
Cognitive Behavioral Management
of Chronic Pain
41.2
38.2*
34.9*
• Six weekly 90-minute
group sessions
• Based on CBT Attention
management manual
31.9*
*P<0.05
Pre-treatment
Post-treatment
7.1
6.1*
5.6*
*
3 month Follow-up
5.7*
6 month Follow-up
Average Pain (0-10 scale) n=18
Pain-related Anxiety (Pass-20)
n=20
N=41; data for individuals completing 6-month follow-up
Elomaa MM, et al. Eur J Pain. 2009;13(10):1062-1067.
36
Mind-Body Intervention for Older Adults
with Chronic Pain
Change from Baseline Scores
Comparison group n=37
Worsening
Intervention group n=41
0.91
0.37
-0.64
-0.88
-1.21
Improvement
-1.50
Depression
Anxiety
Pain Interference
CES-D
STAI
BPI-Interference
Berman RLH, et al. J Pain. 2009;10(1):68-79.
37
Long-term Benefits of Psychotherapy in
FM (12-Month Follow-up Data)
Cognitive Behavioral
Therapy (CBT)
Operant Behavioral
Therapy (OBT)
Attention
Placebo (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.
38
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.
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
Exercise: a Meta-analysis of Studies
Worsening (%)
0
Improvement (%)
Aerobic Performance
17.1
0.5
Tender Point Pain
Pressure Threshold
28.1
-7.0
Improvement in Pain
11.4
-1.6
Control group
Exercise intervention group
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?
Outcome
Effect Size
(# Study Arms/# Patients)
-0.24
(P=0.10)
Pain (13/664)
Fatigue (4/200)
Sleep (4/141)
Depressed mood (12/631)
0.05
(P=0.71)
-0.15
(P=0.50)
-0.24
(P=0.004)
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.
43
Tai Chi in Chronic Pain: Demonstrated
Effectiveness of a Mind-Body Intervention
12 weeks,
twicen=33
weekly,
Tai Chi group,
60-minute
Taigroup,
Chi sessions
vs
Control
n= 33
wellness education and stretching
Improvements were maintained at
FIQweeks
at 12 weeks
(P<0.001)
24
(P<0.001)
Chenchen W, et al. N Engl J Med. 2010;363(8):743-754.
FIQ = FM impact questionnaire.
44
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.
45
Pharmacological Treatment Options for
Anxiety and Mood Disorders
• Lorazepam
• Clonazepam
• Alprazolam
•
•
•
•
•
TCAs (many)
Venlafaxine
Duloxetine
Desvenlafaxine
milnacipran
Benzos
SSRIs
SNRIs
α2δ
ligands
•
•
•
•
•
Fluoxetine
Sertraline
Paroxetine
Citalopram
Escitalopram
• Gabapentin
• Pregabalin
46
Multidisciplinary Treatment: Impact on
Improvement and HPA Changes
3 weeks of multidisciplinary treatment consisted of education,
stretching, CBT, relaxation training, and aerobic exercise
48.9
*
57.3
63.1
64.1
69
Before admission and treatment
Before treatment
After treatment
*P<0.05
13.3
22.4
*
*
5.5
13.3
13.5
24.9
38
*
Positive
Tender
Points (n)
VAS
Score
(1-100)
% of Pain
Area
CES-D
Score
(0-60)
N=12.
CBT=cognitive behavioral therapy; CES-D=Center for Epidemiologic Studies Depression Rating Scale.
Bonifazi M, et al. Psychoneuroendocrinology. 2006;31:1076-1086.
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
Pharmacological
treatment(s)
Nonpharmacological
treatment(s)
If Anxiety still
persists
49
Scales for Diagnosing Anxiety
and Depression
GAD-7
HADS
PHQ-9
50
A Clinically Useful Anxiety Screener:
GAD-7
Kroenke K, et al. Ann Intern Med. 2007;146:317-325.
51
GAD-7: Useful in Detecting Multiple
Anxiety Disorders
Sensitivity
GAD-7 Score of ≥8
Specificity
0.92
0.76
Generalized Anxiety
D/O
Kroenke K, et al. Ann Intern Med. 2007;146:317-325.
0.82
0.75
Panic
D/O
0.78
0.74
Social Anxiety D/O
0.76
0.75
PTSD
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
PHQ-9
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
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
0-4
5-9
10-14
15-19
20-27
Depression Severity
None
Mild
Moderate
Moderately Severe
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
In Conclusion:
56
Pain
Fatigue
Sleep
Metabolic
Cognitive
Optimum would be early, full, and sustained control over ALL symptoms
57
What Are We Treating When We “Treat”
a Patient ?
Sleep
disturbance
Metabolic
syndrome
Pain
Fatigue
Cognitive
disturbance
58
Encountering, and Conquering “Pseudomedication” Failure
 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
 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
59
Target Symptoms and Shared Neurobiology
of Chronic Pain and Depression
Genetic
predisposition
Poor sleep
Trauma
Neuroendocrineimmune
dysfunction
Infections,
Inflammation
Hyperexcitement of
central neurons
Other
factors
ANS
dysfunction
Psychological
factors, stress
Neonatal,
Childhood trauma
Environmental,
Chemical
Central
sensitization
Central
sensitization
Other
mechanisms
CSS
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

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