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Initial Findings fromVol. XXI, Issue 1 the OPPERA Study:
VOL XI NO• Medicine
1 JUNE
• 2013
Editorial Board
Implications
for Translational Pain
P
Editor-in-Chief
ain researchers and clini-
Jane C. Ballantyne, MD, FRCA
cians have over the
Anesthesiology, Pain Medicine
USA
last
several decades advanced our
Advisory Board
knowledge
and abilities to as-
sessMichael J. Cousins, MD, DSC
the underlying neural mechanisms
June 2013
Psychosocial Aspects of Chronic Pelvic Pain
many common chronic pain conditions,
is a mosaic of measurable clinical signs
and symptoms that can be viewed as
Pain is unwanted, is unfortunately common, and remains essential for survival (i.e.,
a set
of intermediate
phenotypes
evading
danger) and
facilitatingthat
medical diagnoses. This complex amalgamation of
andAustralia
putative etiological pathways that
aresensation,
temporally
influenced
environemotions,
andby
thoughts
manifests itself as pain behavior. Pain is a motimental events such as history of injury, 1
mediate temporomandibular disorder
infections, life-relevant stressors,
(TMD) and other persistent or chronic
and a variety of chemical exposures.11
pain conditions. What has emerged is
Environmental events or exposures in
a model that recognizes that TMD, like
turn influence the expression patterns
Pain Medicine, Palliative Medicine
vating factor for physician consultations and for emergency department visits and is
a variety of signaling pathways that
What Are the Phenotypic,
Genetic, and Environmental
Variables that Define or
Characterize the Signs and
Symptoms of TMD?
manifest as quantitative and quali-
Case-control studies have identified
tative intermediate phenotypes that de-
several intermediate phenotypes that
fine the TMD patient at a specific point
differentiate TMD cases from non-
in time. With the progression of time,
TMD cases.3 Recent findings from the
the types and degree of exposure to en-
Orofacial Pain: Prospective Evalua-
vironmental exposures accumulate, re-
tion and Risk Assessment (OPPERA)
sulting in the signs and symptoms that
case-control study of chronic TMD
Center for Pain Research and Innovation,
University of North Carolina at Chapel Hill,
Chapel Hill, N. Car., USA
define a TMD patient. With time and
demonstrate that people with chronic
with exposure to both protective ex-
TMD differ from people without TMD
University of Florida, College of Dentistry,
and Pain Research and Intervention Center
of Excellence, Gainesville, Fla., USA
posures (e.g., treatments) and negative
across multiple phenotypic areas
influences (e.g., tobacco smoke), there
including, but not limited to, sociode-
are temporally dependent changes in
mographic factors, clinical variables,
the severity of self-reported facial pain,
psychological functioning, pain
disability, and related comorbid condi-
sensitivity, and autonomic domains.
tions. The successful diagnosis and
The strongest associations with TMD
William Maixner, DDS, PhD1
Roger B. Fillingim, PhD2
Anne E. Sanders, PhD3
Eric Bair, PhD1,4
Joel D. Greenspan, PhD5
Richard Ohrbach, DDS, PhD6
Ron Dubner, DDS, PhD5
Luda Diatchenko, MD, PhD1
Shad B. Smith, PhD1
Charles Knott, MPA7
Gary D. Slade, BDSc, PhD1,3,8
1
2
Department of Epidemiology, University of
North Carolina at Chapel Hill, Chapel Hill,
N. Car., USA
3
Department of Biostatistics, University of
North Carolina at Chapel Hill, Chapel Hill,
N. Car., USA
4
of multiple genes and the activity of
treatment of TMD patients requires an
were observed for measures related
Department of Neural and Pain Sciences,
and Brotman Facial Pain Clinic, University
of Maryland Dental School of Dentistry,
Baltimore, Md., USA
understanding of the risk factors (ge-
to bodily tenderness (e.g., pressure
netic and environmental) that mediate
pain thresholds; Fig. 1) and salience of
the biological processes regulating the
symptoms (e.g., somatic awareness).
Department of Oral Diagnostic Sciences,
University at Buffalo, Buffalo, New York,
USA
expression of intermediate phenotypes
Weaker associations with chronic
that define the signs and symptoms of
TMD emerged for measures of mood,
Battelle Memorial Institute, Durham,
N. Car., USA
TMD. Empowered by years of knowl-
autonomic function, temporal regula-
edge generated from both clinical and
tion of pain, and genetic variants. The
basic science discoveries, we have
broad range of phenotypic domains
begun this quest.
that distinguish chronic TMD cases
5
6
7
Department of Dental Ecology, University
of North Carolina at Chapel Hill, Chapel
Hill, N. Car., USA
8
PAIN: CLINICAL UPDATES • DECEMBER 2014
1
Fig. 1. Pressure pain thresholds (PPTs) derived at 10 body sites for temporomandibular disorder (TMD) cases (red, N = 186) and a sample of control subjects without TMD (blue, N = 1621) derived
from 25,103 questionnaires in the OPPERA study. Bars depict mean and standard error. In all cases, TMD cases have lower PPTs than controls, in both cranial and extracranial sites. (All P < 0.001.)
TMD Cases
Controls
from controls reflects the complex,
conditions, a greater number of non-
measures emerged as the most impor-
heterogeneous, and multidimensional
specific orofacial symptoms, and higher
tant predictors. TMD incidence was
nature of TMD etiopathogenesis,
scores on the bodily pain scale from the
strongly associated with the SF-12v2
which we have referred to as a “web
Short Form-12 Health Survey, version
bodily pain subscale, a single question
of causation.”9
2 (SF-12v2). The first two measures are
about the degree to which pain inter-
notable because they are simple check-
feres with work.
OPPERA investigators also
measured the incidence of TMD in a
lists of commonly occurring health-
prospective cohort study of first-onset
related conditions, rather than precise,
several genetic associations with TMD
TMD.16 The study design permits
psychometrically validated measures
case status, providing important clues
evaluation of the temporal sequence
of a specific construct. Specifically, the
as to the biological pathways that may
between putative cause and develop-
checklist of 20 comorbid conditions,
contribute to the molecular etiology of
ment of TMD, unlike the case-control
which was created for the OPPERA
TMD.18 The association analysis with
study design, which cannot distinguish
study, includes both painful conditions
chronic TMD provided evidence sup-
bidirectional or reverse relationships
(e.g., irritable bowel syndrome) and
porting two genes previously reported
between TMD and risk factors. In the
other conditions that are not primar-
to contribute to related conditions:
prospective cohort study, pain symp-
ily painful (e.g. depression). The list
serotonin receptor 2A (HTR2A), which
toms were monitored closely using
of six nonspecific orofacial symptoms
encodes a receptor for the neurotrans-
quarterly (three-monthly) question-
includes aversive sensations of the
mitter serotonin; and catechol-O-meth-
naires that were completed by 2737
face and jaw that are not primarily
yltransferase (COMT), which encodes
study participants who had no history
painful (e.g., fatigue and stiffness)
an enzyme that regulates levels of cat-
of TMD at enrollment. Facial pain
or that reflect sub-pain symptoms
echolamines, including the neurotrans-
symptoms occurred at six times the
(e.g., soreness or tenderness). These
mitters dopamine, epinephrine, and
The case-control study revealed
expected rate when both headache and
other bodily pain were also reported
(Fig. 2). The quarterly questionnaires
revealed a “symptom iceberg” of facial
pain in the community: one third of
study participants reported at least one
month in which they had facial pain
for at least five days per month; moreover, most of them did not seek health
care or use analgesics.17
Participants who reported facial pain symptoms were invited to
research clinics where trained examiners identified 260 cases of first-onset,
clinical TMD—an overall rate of 3.5% of
people per annum. Variables from the
health status domain made the greatest contribution to predicting incident
clinical TMD, followed closely by the
psychosocial and clinical orofacial
domains. Sociodemographic, pain sensitivity, and cardiac autonomic function
domains made smaller contributions.
Among the individual variables, three
stood out as the most important predictors: a greater number of comorbid
PAIN: CLINICAL UPDATES • DECEMBER 2014
Fig. 2. Pain symptom episodes reported in quarterly screening questionnaires in the OPPERA
prospective cohort study. Painful temporomandibular disorder (TMD) symptoms were reports of
TMD-like pain lasting ≥5 days per month for ≥1 month of the reporting period. Headaches are reports of ≥5 headaches within the most recent month of the reporting period. Body pain was a report
of pain in ≥1 of 10 body locations lasting for ≥1 days in the same reporting period. Multiplication
numbers in white rectangles represent the ratio of the observed number of overlapping episodes
relative to the expected number of episodes that would have occurred had the symptoms occurred
independently.
3
norepinephrine. Other genes emerged
rs10809907). However, investigators
While the pain field has advanced
as potential new genetic risk factors for
should examine the observed associa-
significantly in measuring molecular
TMD, including glucocorticoid receptor
tions with intermediate phenotypes
and phenotypic signatures associated
(NR3C1), calmodulin-dependent protein
in other cohorts before concluding a
with chronic pain conditions, there is
kinase 4 (CAMK4), muscarinic cholin-
true association.
still a substantial need to identify and
ergic receptor (CHRM2), interferon-
The knowledge generated by these
to measure key environmental expo-
related developmental regulatory 1
genetic association studies furthers our
sures that contribute to the onset and
(IFRD1), and G-protein coupled receptor
understanding of the putative genetic
chronicity of chronic pain conditions
kinase 5 (GRK5).
architecture and associated molecular
such as TMD.
In the prospective study, genetic
mechanisms that contribute to the on-
The initial outcomes of the OP-
variants were investigated for their
set and persistence of TMD. By impli-
PERA study show unequivocally that
association with two sets of outcomes
cation, these mechanisms might also
TMD is a complex disorder that is best
related to the risk of first-onset
contribute to other common persistent
envisaged within a biopsychosocial
TMD: clinically classified first-onset
pain conditions. Understanding the
model of illness, which acknowledges
TMD and five “intermediate pheno-
molecular basis of etiological pathways
the influence of genetic and envi-
types” measured at enrollment that
will permit the development of new
ronmental factors. It is a misnomer,
emerged as predictors of clinical
therapeutic approaches for treating
and no longer appropriate, to regard
TMD. The five intermediate pheno-
conditions such as TMD, along with
TMD solely as a localized orofacial
types were: (1) the number of comor-
related common chronic pain condi-
pain condition. For the majority of
bid health condition14; (2) the number
tions that are highly prevalent with
people with chronic TMD, the condi-
of nonspecific orofacial symptoms12;
TMD and share common pathophysi-
tion is a multisystem disorder with
(3) global psychological symptoms2;
ological processes.
overlapping comorbidity. One of the
(4) stress and negative affect2; and
A variety of environmental influ-
clinical challenges is to distinguish
(5) heat pain temporal summation.5
ences or exposures are related to risk
incidental findings from those that
The latter three measures were latent
of TMD onset or chronicity. History
have prognostic or etiological signifi-
constructs obtained from principal
of injury to the jaw, as reported on
cance, which will require relatively
component analysis. While no single
study entry, was associated with TMD
large-scale prospective studies that
nucleotide polymorphism (SNP) was
case status but not with TMD onset.
are sufficiently powered to identify
significantly associated with risk of
Increased TMD incidence was associ-
risk factors that predict or contrib-
TMD onset, several SNPs exceeded
ated with greater digit length ratio
ute to the processes that mediate the
false discovery rate thresholds for
(D2:D4), a marker of elevated estro-
transition from acute to chronic pain.
association with an intermediate phe-
gen relative to testosterone in utero.
A clear picture is emerging that TMD
notype.19 A SNP encoding a sodium
However, digit length ratio did not
is a mosaic of diverse symptoms and
channel protein (SCN1A, rs6432860)
differentiate chronic TMD cases from
health-related characteristics that are
was significantly associated with
controls. Current or former smokers
strong predictors of first-onset TMD,
nonspecific orofacial symptoms, as
had a greater risk of developing TMD
and not merely consequences of TMD.
was a SNP encoding an angiotensin
in comparison to those who had never
The degree to which these markers
enzyme (ACE2, rs1514280). Another
smoked. One mechanism by which
of onset predict the transition to a
SNP encoding enzymes that catalyze
these exposures might influence pain
more severe and chronic form of TMD
the conversion of arachidonate to
is through epigenetic effects on pain-
remains an open question.
prostaglandin (PTGS1, rs3842803)
signaling pathways. Finally, chrono-
was significantly associated with
logical age, which may represent a
global psychosocial symptoms, as was
measure of the time epoch that an in-
a SNP encoding an amyloid precur-
dividual has experienced and biologi-
sor protein (APP, rs466448). Finally,
cally responded to both negative and
temporal summation of heat pain
positive environmental exposures, was
Case-control and prospective cohort
was significantly associated with a
positively associated with TMD case
studies such as OPPERA can pro-
multiple PDZ domain protein (MPDZ,
status and the risk of developing TMD.
vide important clues regarding the
4
How Can We Translate the
Results of Population-Based
Cohort Studies into Clinical
Practice?
PAIN: CLINICAL UPDATES • DECEMBER 2014
etiological mechanisms that contrib-
one or more phenotypic measure,
ute to the onset and persistence of a
has been applied to measures of pain
variety of pain conditions. OPPERA
sensitivity made using quantitative
has collected over 200 phenotypic
sensory testing (QST).7 The findings
variables and approximately 3500
demonstrate that people can be strati-
genetic variables from several thou-
fied based on responses to multiple
sand individuals. Several interesting
stimulus modalities. Several studies
findings have and will continue to
have reported such analyses in fi-
emerge from this data set, but how do
bromyalgia, low back pain, and TMD,
we translate all of this information
including clustering of patients ac-
into clinically useful tools that will
cording to physical and psychosocial
assist clinicians with the diagnosis
symptoms,15,20–22 QST responses and
and treatment of patients with TMD
comorbid symptoms,4,13 and biological
and related conditions? First, we must
markers and psychologically assessed
account for the fact that TMD is a
factors.10 Although the nature of the
multisystem disorder with overlap-
subgroups identified varies across
ping comorbidity that is dictated by
studies owing to differences in the
the nature and types of environ-
phenotypes used to generate the
mental exposures combined with the
clusters, these studies demonstrate
individual’s genetic susceptibility to
the feasibility of deconstructing the
Maree T. Smith, PhD
express the mosaic of intermediate
heterogeneous TMD population into
Pharmacology
Australia
phenotypes that characterizes a TMD
more homogeneous subgroups. Other
patient. It is clear that TMD patients,
methods of classification are avail-
as well as individuals with related
able, including latent class analysis
chronic pain conditions, represent a
and machine learning approaches.6,8
heterogeneous population of patients
The genetic and associated molecular
reporting orofacial pain. Advanced
pathways that underlie the identi-
methods of data analysis need to be
fied affected subgroups have not yet
applied to the multiple phenotypic
been adequately assessed. Neverthe-
domains (psychological, pain sensitiv-
less, the identification of diagnostic
ity, autonomic, and clinical) to reveal
subgroups using clinically practical
more homogeneous subgroups within
measures of intermediate phenotypes
the population. Each domain can be
coupled with the identification of the
examined and interpreted indepen-
molecular profiles that underlie spe-
dently; however, the findings can also
cific subgroups holds great promise
be examined across domains in order
in developing mechanistic diagnostic
to identify patient profiles or mosa-
protocols and identifying novel bio-
ics that reflect differing pathophysi-
logical targets and pathways for both
ological mechanisms and distinct
pharmacological and nonpharmaco-
underlying genetic and molecular
logical therapeutic interventions.
architectures. Statistical approaches
can be applied to identify profiles
across phenotypic domains that reflect subpopulations of TMD patients.
What Is on the Horizon for the
Diagnosis and Treatment of
TMD and Related Disorders?
For example, cluster analysis, a set
The OPPERA team believes that the
of statistical classification methods
future is bright for making major
to identify groups of people that
headway with respect to new and
show similar characteristics across
clinically useful diagnostic tools and
PAIN: CLINICAL UPDATES • DECEMBER 2014
Editorial Board
Editor-in-Chief
Jane C. Ballantyne, MD, FRCA
Anesthesiology, Pain Medicine
USA
Advisory Board
Michael J. Cousins, MD, DSC
Pain Medicine, Palliative Medicine
Australia
Maria Adele Giamberardino, MD
Internal Medicine, Physiology
Italy
Robert N. Jamison, PhD
Psychology, Pain Assessment
USA
Patricia A. McGrath, PhD
Psychology, Pediatric Pain
Canada
M.R. Rajagopal, MD
Pain Medicine, Palliative Medicine
India
Claudia Sommer, MD
Neurology
Germany
Harriët M. Wittink, PhD, PT
Physical Therapy
The Netherlands
Publishing
Daniel J. Levin, Publications Director
Elizabeth Endres, Consulting Editor
Timely topics in pain research and treatment
have been selected for publication, but the
information provided and opinions expressed
have not involved any verification of the findings, conclusions, and opinions by IASP. Thus,
opinions expressed in Pain: Clinical Updates do
not necessarily reflect those of IASP or of the
Officers or Councilors. No responsibility is assumed by IASP for any injury and/or damage
to persons or property as a matter of product
liability, negligence, or from any use of any
methods, products, instruction, or ideas contained in the material herein.
Because of the rapid advances in the
medical sciences, the publisher recommends
independent verification of diagnoses and
drug dosages.
© Copyright 2014 International Association
for the Study of Pain. All rights reserved.
For permission to reprint or translate
this article, contact:
International Association
for the Study of Pain
1510 H Street NW, Suite 600,
Washington, D.C. 20005-1020, USA
Tel: +1-202-524-5300
Fax: +1-202-524-5301
Email: [email protected]
www.iasp-pain.org
5
therapies for treating TMD and related
continuing revolution in our under-
In addition, we express our gratitude to
conditions. New diagnostic methods ca-
standing of the molecular basis of pain
the participants who have devoted time
pable of accurately classifying patients
conditions will result in the identifica-
and effort in support of this research.
into discrete subpopulations based on
tion of new subgroup specific drug
biopsychosocial phenotypes in addition
targets and the development of new
Disclosures
to anatomically specified criteria will
drugs, biologics, and procedures that
This work was supported by NIH grant
soon become available. We envision
are effective in treating large subpopu-
U01DE017018. The OPPERA program
that these additional tools will provide
lations of TMD patients. The success of
also acknowledges resources specifically
clinicians with a new way of diagnos-
this process will require a close symbi-
provided for this project by the respec-
ing and identifying treatment algo-
otic relationship between clinical and
tive host universities: University at Buf-
rithms based on patient subtype rather
basic scientists for the translational
falo, University of Florida, University of
than only on a diagnosis according to
process to be fully effective.1 In our
Maryland-Baltimore, and University of
anatomical site (e.g., lower back pain,
view, the quest for translational pain
North Carolina-Chapel Hill. Gary Slade
irritable bowel syndrome, or TMD).
treatment is in its infancy but shows
and Roger Fillingim are consultants
Methods that are feasible in the clinical
great promise in developing new diag-
and equity stock holders, and William
setting and that predict the likelihood
nostic methods and therapeutics.
Maixner and Luda Diatchenko are
of clinical pain progression from acute
cofounders and equity stock holders in
to chronic status are also close at hand.
Acknowledgments
In parallel with the development of
The authors would like to thank the
ing research services in personalized
methods that permit the identification
OPPERA research staff for their
pain medication and diagnostics. Other
of subpopulations of TMD patients, the
invaluable contributions to this work.
authors report no conflicts of interest.
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