“divide no more” cross talk between pain, anxiety, depression & insomnia “divide no...
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Chronic Pain: Prevalence in the Community
1Blyth FM, et al. Pain. 2001;89(2-3):127-134; 2Elliott AM, et al. Lancet. 1999;354(9186):1248-1252; 3Gerdle B, et al. J Rheumatol. 2004;31(7): 1399-1406; 4OPENMinds. Pain in Europe–a public health priority. Mundipharma International Limited, 2011; 5Bouhassira D, et al. Pain. 2008;
136(3):380-387; 6Moulin DE, et al. Pain Res Manag. 2002;7(4):179-184; 7Johannes CB, et al. J Pain. 2010;11(11):1230-1239.
46.5%
53.7%
26% 30%
30.7%CHRONIC PAIN
31.7%
M:17.1%
F:20%
M:27%
F:31%
*Data show odds ratio with 95% confidence intervals.
World Mental Health Survey (N=42,249)
0
1
2
3
4
5
6
Asthma HTN Arthritis Heart Disease Back/Neck Pain Chronic Headache
Multiple Pains
Odd
s Rati
o*
P<.05 for all comparisons vs. persons with neither depression nor anxiety
Depression and anxiety
DepressionAnxiety
HTN=hypertension.Scott KM et al. J Affect Disord. 2007;103:113-120.
Anxiety & Depression are HIGHLY Associated with Physical Conditions and Symptoms
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 Anxiety and activities of daily living
N=570 individuals >18 years, reporting insomnia in the past 12 months.
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
Pain Condition (Headaches) and Psychiatric Disorders
Kalaydjian A, Merikangas A. Psychosom Med 2008;70(7):773-780.
Major De-pression
Panic D/O Generalized Anxiety D/O
1.0 1.0 1.0
2.84
3.293.03
Ad
just
ed o
dd
s ra
tio
n=15,330 - without headaches
n= 3,045 - with headaches
No Pain n=50
Chronic Pain n=40
2.0
4.6
3.1
5.4HADS-depression scoreHADS-anxiety score
Mea
n sc
ore
*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 subsyndromic) had chronic pain
**
Chronic Pain After Accidental Injury & Its Relationship To Anxiety / Depression
Jenewein J, et al. J Psychosom Res. 2009;66(2):119-126.
“Ring of Fire”: Odds Ratio of Psychiatric Comorbidities in FM
Arnold LM, et al. J Clin Psychiatry. 2006;67(8):1219-1225.
FibromyalgiaAny
Anxiety Disorder
6.7
Eating Disorder
2.4
Substance Use
Disorder 3.3
Major Depressi
on2.7
N = 108 with fibromyalgia, 228 without fibromyalgia
Mild Moderate Severe
6.1
7.9
10.3
6.7
8.9
11.0HADS-depression scoreHADS-anxiety score
*
BPI – DPN Average Pain Severity
Sco
re
** *
HADS = Hospital Anxiety and Depression Scale; BPI = Brief Pain Inventory
N = 255
DPNP Patients – Relationship Between Pain & Mental Disorders
Gore M, et al. J Pain Symptom Manage. 2005;30(4):374-385.
*p<0.05
Is Pain Affected by the Co-occurrence of Anxiety and/or Depression?
Bair MJ, et.al. Psychosom Med. 2008;70(8):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
**
* *
**
Temporal Sequence of Anxiety Disorders Onset and Co-morbid Physical Conditions
72.0
69.7
61.8
58.8
73.6
73.4
61.8
63.7
64.3
Hypertension
Cardiac diseases
Respiratory diseases
Gastrointestinal diseases
Diabetes
Arthritic conditions
Allergic conditions
Migraine headaches
Thyroid diseases
Comorbid Cases Where Anxiety Disorder Preceded Physical Condition, % (95% CI)
CI=confidence interval.Sareen J et al. Arch Intern Med. 2006;166:2109-2116.
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 (HAD Anxiety sub-score) Depression (HAD Depression sub-score)
Sleep (Sleep Problem Scale)
15-month prospective study, 3171 followed, 324 developed chronic widespread pain
Odds
ratio
Odds ratio
Odds
ratio
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
A Closer Look at Shared Anatomy: Complex Circuits Involve Sensory, Cognitive and Emotional Regions
Apkarian AV et al. Eur J Pain 2005;9:463-84
SECmodel
• Sensory• Emotional• Cognitive
SC
E
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.
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
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
Good News – Yes! Improved Structural & Cognitive Functioning Post Treatment
Seminowitz DA, et al. J Neurosci 2011;31(20):7540-7550
COGNITIVE BEHAVIORAL THERAPY Is It Effective In Chronic Pain?
It is with Depression and Anxiety and Insomnia
Does CBT Impact the Brain of a Chronic Pain Patient? Answer: Yes
DFPFC = Dorsolateral Pre Frontal Cortex, SMA = Sensory Motor Association Cortex. Seminowicz DA, et al. J Pain. 2013;14(12):1573-1584.
Voxel-based morphometry to compare anatomic MRI scans of 13 patients with mixed chronic pain types before and after an 11-week CBT treatment
and to 13 healthy control participants
Not Only That, CBT Also Reduces Catastrophizing and This Has Brain Correlates
Seminowicz DA, et al. J Pain. 2013;14(12):1573-1584.
IFG, inferior frontal gyrus; S1, primary somatosensory cortex; S2, secondary somatosensory cortex.
Neural Sleep-Promoting Pathways
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.
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 Hypometabolism 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
Recognition of neuropathic pain may be challenging for many clinicians:
Proportion of physicians finding it difficult to recognize NeP
0 10 20 30 40 50 60 70
2010 4030 500 60 70
General practitioner
Oncologist
Rheumatologist
HIV specialist
Neurologist
Endocrinologist
Pain specialist
Area of expertise
Percentage of physicians
Prevalence of Neuropathic Pain
Painful Diabetic Neuropathy (PDN)• Painful diabetic neuropathy occurs in up to 26% of all people with
diabetes1
• Diabetes is a significant healthcare problem in Africa and the Eastern Mediterranean / Middle East regions, affecting:
– An estimated 35 million people (5% of the adult population) in 20072
– A predicted 63 million people (6% of the adult population) by 20252
Low back pain• In patients with chronic low back pain, 37% may have predominantly
neuropathic pain3
Postherpetic Neuralgia (PHN)• Neuropathic pain affects 25-50% of people over 50 who have had
herpes zoster4
1. Davies M, et al. Diabetes Care. 2006;29:1518-22.2. International Diabetes Federation. Diabetes Atlas. 3rd ed. Brussels (Belgium); 2006.3. Freynhagen R, et al. Curr Med Res Opin. 2006;22:1911-20. 4. Schmader KE. Clin J Pain 2002; 18(6):350-54.
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
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
Anxiety, Stress, Neuroendocrine, and Immune Dysfunction as Potential Pain Mediators
Yunus MB. Semin Arthritis Rheum 2007;36:339-56
Genetic predisposition
Neuroendocrine- immune
dysfunction
Central sensitivity syndromes
ANS dysfunctionPoor sleep
TraumaPsychological factors, stress
Infections, Inflammation
Neonatal, Childhood
trauma
Otherfactors
Hyperexcitement of central neurons Environmental,
ChemicalCentral
sensitization
Central sensitization
Other mechanisms
Successful Management of Neuropathic Painhas a Positive Impact for the Patient
The earlier a diagnosis is made, the moreopportunities there are to improve patient outcomes.
Treatment of underlying conditions and of pain symptoms
Assessment/ Diagnosis
Improvedquality ofsleep
Improved overall quality of life
Improved physical functioning
Improved psychological state
Reduced pain
38
Effects of Chronic Pain on the Patient
MoodsDepressionAnxietyAngerIrritability
Social FunctioningDiminished social relationships (family/friends)Decreased sexual function/intimacyDecreased recreational and social activities
Societal ConsequencesHealth care utilizationDisabilityLoss of work daysSubstance abuse
Physical FunctioningMobilitySleep disturbancesFatigueLoss of appetite
Ashburn and Staats. Lancet, 1999;353(9167):1865-9 39