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The Epidemic of Chronic Pain: Translational Challenges & Opportunities
Roger B. Fillingim, PhDProfessor, UF College of Dentistry
Director, PRICE
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Overview of Presentation
• Chronic pain as an epidemic
• Translational approaches in pain research– Challenges– Opportunities
• Translational Bridges
• The way forward
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What is Chronic Pain?
• Chronic pain has been recognized as that pain which persists past the normal time of healing (Bonica,1953). In practice this may be less than one month, or more often, more than six months. With nonmalignant pain, three months is the most convenient point of division between acute and chronic pain, but for research purposes six months will often be preferred.
Merskey & Bogduk, Eds (1994). IASP Classification of Chronic Pain
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Is Chronic Pain an Epidemic?
• Epidemic (noun): a disease or event whose incidence is beyond what is expected
Mosby's Medical Dictionary, 8th edition. © 2009, Elsevier
• Epidemic (adj.): extremely prevalent; widespreadDictionary.com
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IOM Report: Released June 29, 2011
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Pain as a Public Health Problem
• Finding 2-1. Pain is a significant public health problem – Chronic pain alone affects at least 100 million
U.S. adults, reduces quality of life, affects specific population groups
– Pain costs society at least $560–635 billion annually (an amount equal to about $2,000 for everyone living in the United States)
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Prevalence and Costs of Several Chronic Diseasesin the United States
Cance
r
HIV/AID
S
Heart Dise
ase
Diabetes
Alzheim
er's
Chronic
Pain0
20
40
60
80
100
120
0
100
200
300
400
500
600
700Prevalence Annual Costs
Poin
t Pre
vale
nce
(in m
illio
ns) 2010 Annual Costs (in billions)
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Overview of Presentation
• Chronic pain as an epidemic
• Translational approaches in pain research– Challenges– Opportunities
• Translational Bridges
• The way forward
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How Far Has the Pain Field Come in the Last 20+ Years?
• Mike S. – CLBP for several years– 2 unsuccessful surgeries
– 45 year old former iron worker– < HS education, functionally illiterate– Panic disorder, depression– MI
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Since January 1, 1992 there have been 63,633 articles published on “chronic pain.”
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Then vs. NowThen Now
Surgical Options Lumbar fusion Lumbar fusion
Medications NSAIDs, antidepressants, opioids (available, but not prescribed)
Similar classes of medications, but some new options (duloxetine, milnacipran), gabapentenoids.
Opioids more likely to be used
Neurostimulation Spinal cord stimulation (SCS)
SCS, noninvasive stimulation methods (tDCS, TMS) – but these are not widely available clinically
Behavioral Approaches
Multidisciplinary treatment
Multidisciplinary care is less available now
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Why Such Limited Progress in 20+ Years?
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Pain as a Symptom vs. a Disease
“While pain can serve as a warning to protect us from further harm, it also can contribute to severe and even relentless suffering, surpassing its underlying cause to become a disease in its own domains and dimensions.”
IOM Report (2011), Preface, page ix
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What Is Translational Pain Research?
PainT0
Discove
ry Res
earch T1
Translation to Humans
T2
Transla
tion to Pa
tientsT3-4
Translation to
Practice & Population
Reduced Pain in the Population
Quantitative Sensory Testing
Identify New Molecular Targets
PreclinicalNociceptive Assays
Genetic Associations
Brain Imaging
Basic Neurobiology of Nociception
Case-ControlStudies
Phase II-IIIClinical Trials
Social Determinants
Of Health
ImplementationScience
PragmaticTrials
ComparativeEffectiveness
Trials
Pharmacologic Probes
High Throughput Screening
Prospective Cohort Studies
Genetic Associations
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Translational Challenges & Opportunities
Issue Challenge OpportunityPain research is underfunded XXX XXPreclinical pain models often fail to reflect clinical pain
XXX XXX
Pain is a subjective experience XXX XXXPain is actively modulated by the CNS XX XXXPain is driven by multiple biopsychosocial processes
X XXX
Pain is characterized by robust individual differences
XX XXX
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The First Translational Challenge
Heart Disease Diabetes HIV/AIDS Alzheimer's Cancer Chronic Pain0
1
2
3
4
5
6
7
Societal Costs NIH Funding
2010
Ann
ual C
osts
(in
hund
reds
of b
illio
ns)
2010 NIH
Funding (in billions)
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=?
What’s Impeding Translational Pain Research?
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Challenges to T1 Translation in Pain Research
• Reflex-based nociceptive assays• Failure to model sources of variability in
human pain responses (e.g. socioeconomic influences, psychological factors)
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Pain is a Major Public Health Condition
But, Pain is Also a Private Health Condition
There is no visible blood test or X ray to show a trauma. I do not look sick.
- A person with chronic pain (IOM Report)
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Pain as a Subjective Experience
“The neurologic signature for physical pain has been identified in a new study.”
Wager, et al, 2013 NEJM 368: 1388-97
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Advantages of Self-Report Measures
• Self-report pain measures are reliable and valid
• Cost and convenience
• Epidemiological research
• Validate the person’s experience
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Descending pain pathway (Purves, 2001).
Pain is Actively Modulated in the CNS
Price (2000) Science 288: 1769-72
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Psychosocial Factors Impact CNS Mechanisms
From Tracey & Mantyh (2007) Neuron 55: 377-91
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Psychological Factors
SocialFactors
Biological Factors
Chronic Pain
The Biopsychosocial Model of Pain
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Overview of Presentation
• Chronic pain as an epidemic
• Translational approaches in pain research– Challenges– Opportunities
• Translational Bridges
• The way forward
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Seizing Opportunities in Translational Pain Research
Mechanisms Pain Treatment
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Translational Bridges in Pain Research
• Laboratory pain testing (or Quantitative Sensory Testing, QST)
• Genetics• Brain Imaging• Biopsychosocial factors
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What is Quantitative Sensory Testing?
The assessment of perceptual and/or physiological responses to systematically applied and quantifiable sensory stimuli for the purpose of characterizing somatosensory function or dysfunction.
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Common Experimental Pain Modalities and Measures
Stimulus Modalities Pain MeasuresElectrical Pain ThresholdContact Thermal (heat, cold) Pain ToleranceImmersion Thermal (heat, cold)
Suprathreshold Scaling (e.g. VAS, NRS)
Mechanical/Pressure Temporal SummationIschemic Conditioned Pain ModulationChemical (e.g. capsaicin, hypertonic saline, glutamate)
Cerebral Responses (e.g. EEG, fMRI, PET)
Muscle Reflexes (e.g. R3 reflex)
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Dad, you’re a sick, sick man.
Thermal Pain Assessment
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Don’t let the smiles fool you,
WE NEED HELP!
Ischemic Pain Assessment
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QST IS CLINICALLY RELEVANT
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Understanding Pain and Limitations in OsteoArthritic Disease (UPLOAD) Study
•Heat pain threshold & tolerance•Temporal summation (TS) at three temperatures
Thermal Pain Testing*
•Pressure pain thresholds•Punctate mechanical pain & TS
Mechanical Pain Testing*
•Cold pressor pain at 8, 12, 16 deg C•Ratings obtained at 30 sec & 1-minuteCold Pressor Pain
•Heat TS (left hand) before & after 1-minute immersion in cold water (right hand)
Conditioned Pain Modulation
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Descriptive StatisticsVariable OA High Pain*
(n=155)OA Low Pain*
(n=129)Controls (n=119)
Demographic Variables
Age (Years) 55.4 (7.1) 58.4 (7.9) 57.4 (8.0)
Sex (% Female) 65.3 64.8 63.9
Race (% White)* 27.3 39.2 70.6
Clinical Variables
GCPS-Characteristic Pain (0-100) 67.7 (14.1) 30.6 (12.7) 10.2 (16.8)
GCPS-Disability (0-100) 59.7 (24.5) 24.6 (21.7) 2.1 (7.0)
WOMAC-Pain (0-20) 9.8 (4.1) 4.5 (2.8) 0.6 (1.7)
WOMAC-Physical Function (0-) 31.8 (13.7) 13.9 (10.2) 1.8 (4.8)
SPPB Total Score 9.2 (2.1) 10.5 (1.5) 10.9 (1.4)
CES-D Scores 11.8 (8.3) 7.6 (6.4) 6.5 (6.7)
* High vs. low OA pain based on median split of GCPS-Characteristic Pain Score (median=50)
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Heat Pain Thresholds and Tolerances for OA Patients and Controls
HPTh-Arm HPTh-Knee HPTo-Arm HPTo=Knee38
39
40
41
42
43
44
45
46
47
48
OA-HighOA-LowControl
Tem
pera
ture
(deg
C)
a
b
a
bb
a
bb
Groups with unlike letters differ from each other, p < 0.05
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PPT-medial PPT-lateral PPT-quad PPT-trap PPT-arm0
100
200
300
400
500
600
OA-HighOA-LowControl
a
bb
a
bb a
b
c
a
b
b
aa
b
Pressure Pain Thresholds for OA Patients and Controls
Pres
sure
(kPa
)
Groups with unlike letters differ from each other, p < 0.05
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Punctate Mechanical Pain for OA Patients and Controls
Trial 1 Trial 10 Trial 1 Trial 100
5
10
15
20
25
30
35
40
45
50
OA-HighOA-LowControl
Pain
Rati
ng (0
-100
)
Knee* Hand*
*OA-High differs from the other two groups in both average rating and slope (p < 0.05)
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Temporal Summation of Heat Painfor OA Patients and Controls
Trial 1 Trial 2 Trial 3 Trial 4 Trial 50
10
20
30
40
50
60
OA-HighOA-LowControl
Pain
Rati
ng (0
-100
)
*OA-High differs from the other two groups in both average rating and slope (p < 0.05)
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What are Individual Differences?
• Individual differences refer to variations across people in abilities, attitudes, experiences, behavior, and other potentially important biological or psychological responses
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Pain After Laparascopic Cholecystectomy (Bisgaard, et al, 2001)
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1 14 27 40 53 66 79 92 1051181311441571701831962092222352482612742873003130
10
20
30
40
50
60
70
80
90
100
Ratings of a 48 Degree Thermal StimulusPa
in R
ating
(0-1
00)
Rank
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Brain Correlates of Individual Differences in Pain
Individuals high in sensitivity to thermal pain (HIGH) showed more robust pain-related activation than those low in sensitivity (LOW) in the somatosensory (S1), anterior cingulate (ACC) and prefrontal (PCC) cortex.
(Coghill, et al, 2003, PNAS, 100:8538-42)
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Grey Matter Density and Pain Sensitivity (Emerson, et al, 2014, Pain 155:566-73)
A study of 116 healthy volunteers found that regional grey matter density in the following regions was negatively correlated with pain ratings of a 49 °C heat stimulus: bilateral precuneus, posterior cingulate cortex, inferior parietal lobule, intraparietal sulcus, and primary left somatosensory cortex.
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GENDER DIFFERENCES
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Fillingim, et al, 2009, J Pain, 10: 447-485
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Sex Differences in Chronic Pain Prevalence Across Different Categories (Mogil, 2012, Nat Neurosci Rev 13: 859-66)
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STANDARDIZED PAIN MEASURES ACROSS MULTIPLE PAIN TASKS FOR FEMALES AND MALES
-0.5
-0.25
0
0.25
0.5
HPTH HPTO IPTH IPTO CPTH CPTO PPTTrap PPTMass
Male (96) Female (n=111)
Heat Pain Ischemic Pain Cold Pain Pressure Pain
Mean=0, higher numbers reflect higher pain threshold or tolerance
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Sex Differences in Experimental Pain Measures (Mogil, 2012, Nat Neurosci Rev 13: 859-66)
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Temporal Summation of Thermal Pain (Fillingim, et al, 1998, Pain, 75: 121-27)
p < .005, Trial X Sex Interaction
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Does Pain Increase with Age?
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Prevalence of Chronic Pain Across the Lifespan (Tsang, et al, 2008, J Pain 9:883-91)
18-35 36-50 51-65 66+0
10
20
30
40
50
60
70
MaleFemale
AGE
Prev
alen
ce (%
)
N=42,249 from 17 countries. Chronic pain=presence of at least one of the following in the past 12 months: arthritis or rheumatism, chronic back or neck pain, frequent or severe headaches, other chronic pain.
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Chronic Pain Across the Lifespan (Blyth, et al, 2001 PAIN 89: 127-34)
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60-64
65-69
70-74
75-80
80-84
0
5
10
15
20
25
30
35
MalesFemales
Prev
alen
ce (%
)
Age Group
Interview of 17,543 Australians Chronic pain=Pain experienced every day for three months in the six months prior to interview
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Age-Related Differences in Pain Perception (Edwards & Fillingim, 2003)
Heat Pain Pressure Pain Ischemic Pain
Pain responses compared across multiple modalities in 32 younger (22.4 years) and 34 older (62.2 years) adults.
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Age-Related Differences in Conditioned Pain Modulation(Riley, et al, 2010)
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Prevalence of Migraine by Sex and Age (Lipton, et al, 2001 Headache 41: 646-57)
Age Group
Popu
latio
n Pr
eval
ence
(%)
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GENETIC FACTORS
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Heritability of Pain and Analgesic Responses
Phenotype Heritability Range
Multiple Clinical Pain Conditions (e.g. migraine, neck pain, back pain, widespread pain) 0.34 - 0.68
Experimental Pain (pressure pain, heat pain, cold pain, acid pain, hyperalgesia) 0.10 - 0.60
Opioid Analgesia (tested with heat and cold pain) 0.12 – 0.60
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† Sex X genotype interaction, p’s = .09* Genotype effect, all p’s < .05 for males
OPRM1 A118G Genotype and Pressure Pain Thresholds among Females and Males (Fillingim, et al, 2005, J Pain 6:159-67)
96 F (72 AA, 24 AG/GG)71 M (59 AA, 12 AG/GG)
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Sex X genotype interaction, p < 0.05
OPRM1 A118G Genotype and Heat Pain Ratings among Females and Males (Fillingim, et al, 2005, J Pain 6:159-67)
Male Female0
10
20
30
40
50
60
70
AAAG/GG
Num
eric
al P
ain
Ratin
gs (0
-100
)
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Studied 252 patients presenting with lumbar disc herniation and sciatica
Pain at 12 months was examined as a function of sex and A118G genotype
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Male Female0
1
2
3
4
AAAG/GG
VAS
Ratin
gs (0
-10)
VAS Pain Ratings with Activity 12 Months after Lumbar Disc Herniation
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COMT Haplotype and Pain Sensitivity
LPSAPSHPS
LPS=low pain sensitive, APS=average pain sensitive; HPS=high pain sensitive
Diatchenko, et al. Hum. Mol. Genet. 2005;14:135-143
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PSYCHOLOGICAL FACTORS
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Psychological Factors Predict Development of Chronic Pain
• Low back pain (Linton, 2000, Spine, 25:1148-56; Docking, et al, 2011 Rheumatol 60:1645-53)
• Widespread pain (Jones, et al, 2009 Pain 143:92-96; Mikelsson, et al, 2008 Pain 138:681-87)
• Orofacial pain (Aggarwal, et al, 2010 Pain 149:354-59)
• Abdominal pain (El-Metwally, et al, 2007 Arch Dis Child 92: 1094-98; Nicholl, et al 2008 Pain 137:147-55)
• Headache (Obermann, et al, 2010 Cephalalgia 30: 538-34)
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Orofacial Pain: Prospective Evaluation and Risk Assessment
William Maixner, Co-Program DirectorGary Slade, Co-Program Director
Site PIsRichard Ohrbach, Univ. at BuffaloJoel Greenspan, Univ. of MarylandRoger Fillingim, Univ. of Florida
Core DirectorsGary Slade and Eric Bair: Epidemiology Core
Luda Diatchenko, Bruce Weir, Shad Smith, Dmitri Zaykin : Genomics & Bioinformatics Core
Charles Knott: Data Coordinating Center
External Advisory CommitteeGary Macfarlane, Chair
Funded by NIH/NIDCR: U01 DE017018
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High Psychological
Distress
High State of Pain Amplification
Anxiety
Depression
Stress response
Impaired pain
regulation
Pro-inflammatory
stateAutonomic function
Na+, K+-ATPase
Serotonin transporter
BDNF
12q11.2
Cannabinoid receptors
MAO
11q23
Adrenergic receptorsNMDA POMC
COMT
Interleukins
5q31-32 22q11.21
Opioid receptors ProdynorphinDREAM NGF
IKKNET
Somatization
Neuro-endocrine function
CREB1
Serotoninreceptor GR
Dopamine receptors
Mood
GAD65 CACNA1A
6q24-q25 1p13.1 5q31-q32 9q34.3 Xp11.23
PainfulTMD
Persistent TMD
First-onset TMD
Subclinical signs & symptoms
ENVIRONMENTALCONTRIBUTIONS
Physical environment• eg. trauma, infection
Social environment•eg. life stressors
Culture• eg. health beliefs
Demographics
Diatchenko et al, Pain 123: 226-30, 2006 & Maixner et al, Journal of Pain 12, Suppl 3, 4-11, 2011
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Psychosocial Predictors of First Onset TMD
Global Psych
Symptoms
Stress-
Negative Affect
Passive Pain Coping
Active Pain Coping
0.600000000000001
0.800000000000001
1
1.2
1.4
1.6
1.8
Stan
dard
ized
Haz
ard
Ratio
(+ 9
5% C
I)
Fillingim, et al (2013) J Pain 14:T75-90
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BIOPSYCHOSOCIAL INTERACTIONS
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Combined Influences of COMT and Catastrophizing on Shoulder Pain
• 58 (24 F, 34 M) patients with chronic shoulder pain, undergoing arthroscopic surgery
• Pre-operative testing• Psychological questionnaires (catastrophizing)• Psychophysical testing • Buccal swab for DNA (COMT diplotypes from
Diatchenko, et al, 2005)
• Arthroscopic surgery • Post-operative testing (3-5 months later)
George, et al, 2008, PAIN 136: 53-61
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Combined Influences of Pain Catastrophizing and COMT HaplotypePr
e-O
pera
tive
Pain
Post
-Ope
rativ
e Pa
in
LPS=Low pain sensitive genotype; APS/HPS=Average/High pain sensitive genotype; PCS=Pain Catastrophizing Scale
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Combined Influences of Psychological Factors and COMT Haplotype(George, et al, 2014, J Pain, 15:68-80)
DepressionCatastrophizing
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Overview of Presentation
• Chronic pain as an epidemic
• Translational approaches in pain research– Challenges– Opportunities
• Translational Bridges
• The way forward
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Effect M
odifie
rs (e.g
. sex, ag
e, ra
ce)
Chronic Pain Disorders
Psychological Processes
BiologicalProcesses
Altered Pain Processing
Genetic FactorsEn
viro
nmen
tal E
xpo
sure
s (e
.g. t
raum
a, s
urge
ry)
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Future Directions
• Multiple approaches can facilitate translational pain research in the future:– QST– Brain Imaging– Genetics
• Translational pain research must address the multiple biopsychosocial mechanisms that contribute to chronic pain.
• We need far more T3-T4 pain research.• Through interdisciplinary translational efforts, we can make
rapid progress in addressing the epidemic of chronic pain.
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Acknowledgements
University of North Carolina• Dr. William Maixner• Dr. Gary Slade
University of Alabama at Birmingham
• Dr. Larry Bradley• Dr. Burel Goodin
McGill University• Dr. Jeff Mogil• Dr. Luda Diatchenko
University of Florida• Dr. Roland Staud• Dr. Peggy Wallace• Dr. Joe Riley• Dr. Steven George• Dr. Chris King• Dr. Kim Sibille• Dr. M. Ribeiro-Dasilva• Dr. Toni Glover• Dr. Yenisel Cruz-Almeida
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Thank You