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OROFACIAL PAIN: PROSPECTIVE EVALUATION AND RISK ASSESSMENT (OPPERA)
Supported by NIH/NIDCR U01‐DE017018
National Institute of Dental and Craniofacial Research
202nd Meeting of the
National Advisory Dental and Craniofacial Research Council
Tuesday, January 29, 2013
William Maixner DDS, PhD
Regional Center for Neurosensory Disorders
University of North Carolina
Disclosure: Algynomics Inc. Cofounder and equity shareholder
Temporomandibular Joint Disorders
Temporomandibular Joint Disorders
• TMD – Heterogeneous family of musculoskeletal disorders
– Most common chronic orofacial pain condition
– Highly co‐prevalent with many other chronic pain conditions
• 5%
5% of US adults report TMD symptoms: 6% Females and 2.8% f US d lt
t TMD
t
6% F
l
d 2 8%
Males (Isong U et al, J Orofacial Pain, 2008)
• 10% of NY women had examiner‐diagnosed TMD 10% of NY women had examiner diagnosed TMD (Janal
(J l M et al, J Oral M t l JO l
Rehab, 2008)
• ~ 30
30‐40%
40% of acute cases become chronic
of acute cases become chronic
• Etiology is multifactorial
• Substantial unmet medical need – few effective treatments
Orofacial Pain: Prospective Evaluation and Risk Assessment
d Ri k A
t
William Maixner, Program Director
Site PIs
Richard Ohrbach, Univ. at Buffalo
Joel Greenspan, Univ. of Maryland
Roger Fillingim Univ of Florida
Roger Fillingim, Univ. of Florida
Core Directors
Gary Slade and Eric Bair: Epidemiology Core
Luda Diatchenko, Bruce Weir, Shad Smith, Dmitri Zaykin : Genomics & Bioinformatics Core
Charles Knott: Data Coordinating Center
External Advisory Committee
Gary Macfarlane, Chair
In Response to RFA: DE 05-007 PROSPECTIVE STUDIES ON CRANIOFACIAL PAIN AND DYSFUNCTION
Persistent TMD
Painful
P
i f l
TMD
ENVIRONMENTAL
CONTRIBUTIONS
First-onset
First
onset TMD
Subclinical signs & symptoms
Physical environment
• eg. trauma, infection
Social environment
•eg. life stressors
High Psychological Distress
Culture
• eg. health
beliefs
High State of Pain Amplification
Amplification Demographics
Mood
Anxiety
Stress response
Depression
GAD65 Serotonin
MAO
receptor
Xp11.23 Neuro‐
Impaired Pro‐
endocrine inflammatory pain function Autonomic regulation
state
Somatization
function
Serotonin Cannabinoid Dopamine transporter CACNA1A NET
receptors
receptors
Adrenergic NMDA
GR receptors
DREAM POMC
CREB1
12q11.2 9q34.3 11q23 5q31‐q32 5q31‐32
Opioid receptors
6q24‐q25 Na+, K+‐
ATPase IKK
COMT
BDNF NGF Prodynorphin Interleukins
1p13.1 Diatchenko et al, Pain 123: 226-30, 2006 & Maixner et al, Journal of Pain 12, Suppl 3, 4-11, 2011
22q11.21
Study designs for first‐onset and chronic TMD
Inception cohort:
3,263 people
without TMD
50%
Baseline case‐
control study
control study of chronic TMD
185 baseline cases of chronic TMD
of chronic TMD
Prospective cohort study of first‐onset TMD.
3‐monthly screening questionnaires of all people. Clinical assessment of each person who screens positively and one matched control who screens negatively
260 incident cases of first‐onset TMD
Community-based recruitment of healthy volunteers
Four U.S. study sites
Baltimore, MD; Buffalo, NY; Chapel Hill, NC;
G i
Gainesville,
ill FL
Study-wide screening enrollment criteria
aged 18-44
18 44 years
no significant medical conditions
no recent facial injury
Demographics, Health Status and Clinical Orofacial Characteristics
Onset and Chronic TMD: Age, Gender, Race Associations
•
Odds of chronic TMD was significantly associated with:
– Greater age (OR=2.3, 95%CL=1.5, 3.6) for 35‐44 yr olds relative to 18‐
24
24 yr olds
ld
– Female gender (OR=4.0, 95%CI=2.6, 6.0 relative to males)
– White race (OR=5.0, 95%CL=3.3, 9.8 relative to African‐American)
•
First‐onset TMD was significantly associated with:
– Greater age (HR=1.46, 95%CL=1.03, 2.04) for 35‐44 yr olds relative to Greater age (HR=1 46 95%CL=1 03 2 04) for 35‐44 yr olds relative to
18‐24 yr olds)
And marginally associated with
– Female Gender (HR=1.30, 95%CL= 0.99, 1.69)
F
l G d (HR 1 30 95%CL 0 99 1 69)
– African‐American race (HR=1.37, 95%CL=1.00, 1.87) relative to Whites
•
Health Status Variables as Predictions of First‐onset TMD
Health Status Variables Associated with Chronic TMD
Ohrbach et al, Journal of Pain 2011
Idiopathic pain conditions related (IPCs) to TMD in the OPPERA baseline casecontrol study.
study The four related conditions were: headache,
headache low back pain,
pain
widespread pain and IBS. *OR = odds ratio for TMD in people with 1, 2, 3 or 4 IPCs
relative to people with no IPCs
Clinical Variable Prediction of First‐onset TMD
Psychosocial Domain
Psychosocial Domain
OPPERA Psychological Measures
OPPERA Psychological Measures
Global Psych
Function
Mood/Affect
Stress
Somatic Awareness
Coping
SCL‐90R‐GSI
POMS‐Bi
PSS
Kohn
CSQ‐R
EPQ‐R
State‐Trait Anxiety
LES
PILL
PCS
SCL‐Anxiety
LSL/PCL‐C
SCL‐Somatization IVC
SCL‐Depression
SCL Hostility
SCL‐Hostility
SCL‐90R: Symptom Checklist 90‐Revised, EPQ‐R: Eysenck Personality Questionnaire‐Revised,
POMS‐Bi: Profile of Mood State‐Bipolar, PSS: Perceived Stress Scale, LES: Life Experience Survey, LSL/PCL‐C: Lifetime Stressor List/PTSD Checklist‐Civilian, Kohn: Kohn Reactivity Scale,
PILL: Pennebaker Inventory of Limbic Languidness, CSQ‐R: Coping Strategies Questionnaire‐
Revised, PCS: Pain Catastrophizing Scale; IVC: In‐Vivo Coping
Psychosocial Predictors of First Onset TMD
Standardizeed Hazard Ratio (+ 95% CI))
1.8
1.6
1.4
1.2
1
0.8
06
0.6
Psychosocial Factors Associated with Chronic TMD
Standardizzed Odds Ratio
o (+ 95% CI)
3
25
2.5
2
1.5
1
0.5
Pain Amplification Domain
Pain Amplification Domain
Standardized Hazard Ratios (adjusted for sex, age, race/ethnicity, and study site) for TMD Incidence Related to QST Measures
Standardized Odds Ratios (adjusted for sex, age, race/ethnicity, and study site) for QST Measures Distinguishing TMD Cases from Controls
y
)
Q
g
g
Summary
• 29 of 35 QST measures showed significantly greater pain sensitivity for chronic TMD cases vs controls with most
sensitivity for chronic TMD cases vs. controls, with most odds ratios significant at p<0.001.
• 9 of 35 QST measures showed significantly greater hazard ratios for TMD onset vs. controls, with most differences significant at 0.01<p<0.05.
Genetics Domain
Genetics Domain
Intermediate Phenotype Associations
Non-specific orofacial symptoms
ACE
2
Global psychological factor
PTGS
1
SCN1
A
Windup
Stress factor
APP
MPDZ
Putative Genetic Polymorphims Associated with TMD Case Status
Gene
Protein
Function
NR3C1
Glucocorticoid receptor gene HPA Axis Function and inflammation
HTR2A
Serotonin 2A receptor Pain transmission , TMD, CWP
CAMK4
Calcium/calmodulin‐dependent protein kinase 4 Pain transmission and opioid analgesia
gene
CHRM2
Muscarinic cholinergic receptor 2 Mood and inflammation
IFRD1
Interferon‐related developmental regulator 1 Induced by NFG, neutrophil function
GRK5
G protein‐coupled receptor kinase 5
Regulation of G protein‐coupled receptors including ADRB2
COMT
Catecholamine‐O‐transferase
h l i
f
Pain
i transmission, TMD and opioid
i i
d i id function
f
i
ADRA2C
Alpha‐2C Pain transmission
OPRD
Delta opioid receptor
Pain transmission
IL10
Interleukin 10
Inflammation and Pain
GRIN2A Ionotropic N‐methyl‐D‐aspartate (NMDA) receptor 2A LTP, Pain transmission
Multivariate findings from multiple phenotypic domains
Semi‐Supervised Clustering
• Bair & Tibshirani proposed “semi‐supervised clustering” to choose a relevant subset of the variables when clustering (Bair E, Tibshirani R ,PLoS Biol 2(4), 2004: e108. doi:10.1371/journal.pbio.0020108) • Idea: Perform cluster analysis using only the variables that are d
f
l
l
l h
bl h
most strongly associated with the outcome of interest
• Ensures that the clusters are associated with the outcome
• Removing extraneous variables improves reproducibility
• We have used 15 variables of interest to produce reproducible cluster solutions Three Clusters Identified
• Cluster 1: – Relatively “normal” psychosocial, QST, and autonomic profile
y
py
p
– # M>F and # of Chronic TMD cases > non‐cases
– Chronic TMD cases moderately symptomatic and few comorbid conditions
• Cluster 2: Cl
2
–
–
–
–
Relatively “normal” psychosocial and autonomic profile
Greater muscle pain sensitivity
# M ≈ F and # of Chronic TMD cases ≈
# M ≈
F and # of Chronic TMD cases ≈ non‐cases
non cases
Chronic TMD cases moderately symptomatic and few comorbid
conditions
• Cluster 3: – Relatively abnormal psychosocial, QST, and autonomic profiles
– # F>M and # chronic TMD cases ≈ non‐cases
– Chronic TMD cases very symptomatic and multiple comorbid
Ch i TMD
t
ti
d
lti l
bid conditions
diti
Clinical Characteristics Based on Cluster Assignment
Cluster 1 Means
Cluster 2
Cluster 3
(n=34)
Means (n=115) Means (n=50)
Clinical Variable
Duration of facial pain (months)
Overall PValue
150.50
125.28
99.71
0.136
0-100 average pain over last 2 wks
43 06
43.06
34 56
34.56
52 96
52.96
<0 0001
<0.0001
0-100 highest pain over last 2 wks
62.97
55.57
73.50
<0.0001
0-100 least pain over last 2 wks
16.39
12.26
23.54
<0.002
0-100 current level of facial pain
32.06
21.50
45.00
<0.0001
% of waking day with facial pain
45.15
48.05
71.50
<0.0001
Pain Density = average pain x % waking
day
23.70
19.35
42.28
<0.0001
0-20 Gracely Pain Unpleasantness Scale
8.04
7.37
10.45
<0.0001
0-20 Gracely Pain Intensity Scale
9.56
8.31
12.12
<0.0001
17.15
16.55
20.93
<0.0001
MPQ Sensory
5.01
4.85
6.37
<0.0001
MPQ Current pain level
2 53
2.53
2 41
2.41
3 16
3.16
<0 0001
<0.0001
# of RDC muscle groups + palpation
4.32
5.38
6.00
<0.0001
13.09
20.03
25.00
<0.0001
# of non-RDC + palpation sites
4.21
5.39
9.88
<0.0001
Number of overlapping conditions
2.84
2.24
5.47
<0.0001
MPQ Affect
# of RDC + palpation sites
Bold Black = C1 different from C2; Bold Red = C2 different from C3
199 Chronic Female TMD Cases; Luda Diatchenko’s R01
H
Hazard Ratio (C1 vs
d R ti (C1 C3) for First Onset TMD : OPPERA Cohort
C3) f Fi t O t TMD OPPERA C h t
S
Survival
N = 260 First onset
TMD cases
Observation Years
Cluster Specific Molecular Profiles – Under Investigation
Cluster Contrasts: Genetic Associations
Cluster Contrasts: Genetic Associations
• Genetic associations with several candidate genes were observed in training and validation cohorts – not always the same
OPPERA: cluster 1 vs 3
4.5
4
GABRB3
observed
d ‐log(P)
3.5
CNR1
3
2.5
2
1.5
1
0.5
0
0
1
2
expected ‐log(P)
3
4
Cluster contrasts: Pathway Analysis
Cluster contrasts: Pathway Analysis
• In
In OPPERA, genetic variants in the NF
OPPERA genetic variants in the NF‐κB
κB pathway distinguished cluster 3 from clusters 1 and 2 (overall pathway p=3x10‐4)
1 and 2 (overall pathway p=3x10
Assessed NF‐ κ B Pathway Genes ( i ifi t i l SNP
(significant single SNP p‐values)
l )
NFKB2
REL
RELA
NFKB1
RELB
PIK3R5
PIK3CD
PIK3R4
PIK3C2A
PIK3CG
PIK3C3
PIK3R2
PIK3R1
PIK3R3
PIK3C2G
PIK3CB
PIK3CA
PIK3C2B
IKBKE
IKBKB ( 0 02)
IKBKB (p=0.02)
IKBKG
CHUK (p=0.02)
IKBKAP
AKT1
NFKBIA (p=0.001)
PDPK1
SRC
EGFR (p=0.001)
General Findings and Discoveries •
Multiple biopsychosocical and genetic risk vectors/factors manifest as a diverse mosaic of intermediate/endophenotypes
p
yp ((Signs and Symptoms)
g
y p
)
•
Only some of the factors that predict first‐onset TMD are associated with chronic TMD
•
The basic elements of our proposed heuristic model for TMD onset have been confirmed and extended.
–
–
–
–
Psychological > Pain Sensitivity
Age, gender, race
Health Status
Genetic contributions
•
TMD is not a localized orofacial pain condition
TMD is not
a localized orofacial pain condition
•
TMD is heterogeneous and can be “clustered” into homogenous subgroups •
We are on the verge of identifying new methods for classifying and treating pts W
th
f id tif i
th d f
l if i
d t ti
t
with TMD based on subgroup stratification and biological mechanisms
Publications
• Baseline Case‐Control studyy
– Journal of Pain, Volume 12, Issue 11, Supplement, Pages A1‐A8, T1‐T108 (
(November 2011)
)
– Edited by Samuel F. Dworkin
• Prospective Cohort study
– “Act II” OPPERA findings
– Journal of Pain, Supplement (forthcoming, 2013)
NIH Sponsorship
•
•
•
•
U01‐DE017018 (Maixner, PD)
(
, )
R03‐DE022595 (Slade, PI)
R01‐DE016558 (Diatchenko, PI)
P01‐NS07509 (Maixner, PD)