Systematic Review and Meta-Analysis

Endogenous pain modulation in chronic orofacial

pain: a systematic review and meta-analysis
Estephan J. Moana-Filhoa,*, Alberto Herrero Babilonib, Nicole R. Theis-Mahonc

Abstract
Abnormal endogenous pain modulation was suggested as a potential mechanism for chronic pain, ie, increased pain facilitation
and/or impaired pain inhibition underlying symptoms manifestation. Endogenous pain modulation function can be tested using
Downloaded from https://journals.lww.com/pain by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3GqhOzspyl8wamgPSgXDN0g5u/ix8v83eBLnDIceLOSQ= on 08/09/2018

psychophysical methods such as temporal summation of pain (TSP) and conditioned pain modulation (CPM), which assess pain
facilitation and inhibition, respectively. Several studies have investigated endogenous pain modulation function in patients with
nonparoxysmal orofacial pain (OFP) and reported mixed results. This study aimed to provide, through a qualitative and quantitative
synthesis of the available literature, overall estimates for TSP/CPM responses in patients with OFP relative to controls. MEDLINE,
Embase, and the Cochrane databases were searched, and references were screened independently by 2 raters. Twenty-six studies
were included for qualitative review, and 22 studies were included for meta-analysis. Traditional meta-analysis and robust variance
estimation were used to synthesize overall estimates for standardized mean difference. The overall standardized estimate for TSP
was 0.30 (95% confidence interval: 0.11-0.49; P 5 0.002), with moderate between-study heterogeneity (Q [df 5 17] 5 41.8, P 5
0.001; I2 5 70.2%). Conditioned pain modulation’s estimated overall effect size was large but above the significance threshold
(estimate 5 1.36; 95% confidence interval: 20.09 to 2.81; P 5 0.066), with very large heterogeneity (Q [df 5 8] 5 108.3, P , 0.001;
I2 5 98.0%). Sensitivity analyses did not affect the overall estimate for TSP; for CPM, the overall estimate became significant if
specific random-effect models were used or if the most influential study was removed. Publication bias was not present for TSP
studies, whereas it substantially influenced CPM’s overall estimate. These results suggest increased pain facilitation and trend for
pain inhibition impairment in patients with nonparoxysmal OFP.
Keywords: Endogenous pain modulation, Chronic orofacial pain, Temporal summation of pain, Conditioned pain modulation,
Meta-analysis

1. Introduction societal burden, current knowledge about OFP pathophysiology

Chronic pain has a profound societal impact in the United States
with more adult patients suffering from it than those affected by
heart disease, diabetes, or cancer combined,36 and estimated
treatment costs exceeding $560 billion dollars.22 A significant
part of this scenario is related to orofacial pain (OFP), which
affects about 39 million adults (22%) in the United States.49
Temporomandibular disorders (TMDs) are the most prevalent
OFP conditions after toothache, and they affect approximately
5% to 12% of the population with annual estimates of economic
impact between $4 billion65 and $32 billion.10 Despite this
Sponsorships or competing interests that may be relevant to content are disclosed
at the end of this article.
a
Division of TMD and Orofacial Pain, School of Dentistry, University of Minnesota,
Minneapolis, MN, United States, b Faculty of Dental Medicine, Université de
Montréal; CIUSSS Nord Ile Montreal -Hôpital du Sacré-Coeur de Montréal; CEAMS
E-1300, 5400 Boul Gouin O. Montréal, Canada, c Health Sciences Libraries,
University of Minnesota, Minneapolis, MN, United States
*Corresponding author. Address: Division of TMD and Orofacial Pain, School of
Dentistry, University of Minnesota, 6-320d Moos Tower, 515 Delaware St SE,
Minneapolis, MN 55455, United States. Tel.: 11 (612) 624-3338; fax: 11 (612) 626-
0138. E-mail address: moana004@umn.edu (E.J. Moana-Filho).
Supplemental digital content is available for this article. Direct URL citations appear
in the printed text and are provided in the HTML and PDF versions of this article on
the journal’s Web site (www.painjournalonline.com).
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© 2018 International Association for the Study of Pain
http://dx.doi.org/10.1097/j.pain.0000000000001263
is insufficient to render mechanism-based diagnoses, improved
treatment strategies, or accurate prognosis, which are needed to
appropriately treat these patients and reduce associated health
care costs and side effects related to ineffective treatments.
Up to two-thirds of patients with TMD seek care for their
symptoms and 15% of these patients develop chronic pain.65
Chronic TMD pain usually presents without a clear structural
pathology or disproportionate to physical findings, and may be
considered a “functional disorder” that likely shares pathophys-
iological mechanisms with overlapping chronic pain conditions
such as fibromyalgia, irritable bowel syndrome, and chronic back
pain.1,55,96 Chronic TMD pain usually presents as nonparox-
ysmal, affects more women than men, and current understanding
of its etiology and mechanisms is limited.25 Two other OFP
conditions share similar nonparoxysmal clinical characteristics:
persistent dentoalveolar pain disorder (PDAP) and burning mouth
syndrome (BMS). Persistent dentoalveolar pain disorder is
a persistent pain (.3 months) localized in dentoalveolar regions
currently or previously occupied by teeth in the absence of
detectable pathology,66 with a greater female preponderance
and unclear pathophysiology, despite several proposed theo-
ries.56 Persistent dentoalveolar pain disorder is often present after
endodontic treatment or surgical extraction of teeth. Burning
mouth syndrome is an intraoral burning/dysaesthetic daily
sensation not explained by detectable causal lesions present
.3 months, and it is also more prevalent in women than men and
several etiological mechanisms have been proposed.37,85 Given

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E.J. Moana-Filho et al. 159 (2018) 1441–1455
the similarities in the clinical and demographic characteristics of
TMD, PDAP, and BMS including that they seem to be largely
idiopathic in nature,20 in addition to the fact that both PDAP4,50
and BMS13 are frequently comorbid with TMD, it seems reason-
able to assume shared pathophysiology among these 3 over-
lapping chronic OFP conditions.
Several central nervous system (CNS) mechanisms have been
implicated in chronic pain in general84 and OFP specifically,25,80
including central sensitization, CNS neurotransmitter imbalan-
ces, and somatosensory processing abnormalities.2,25 The latter
includes endogenous pain modulation (EPM), characterized by
the CNS’s ability to modulate nociceptive input from peripheral
tissues, as it ascends to the spinal cord/brainstem and the
brain.59 Endogenous pain modulation can lead to increased or
inhibited pain perception depending on the combined output of
CNS mechanisms involved in nociceptive signal processing, and
it has been suggested that abnormal EPM could be part of
chronic pain pathophysiology.2
Endogenous pain modulation can be tested clinically using
psychophysical methods. To assess pain facilitation, temporal
summation of pain (TSP) can be performed by delivering
suprathreshold noxious stimuli repeatedly in frequencies $0.33
Hz that leads to increased pain perception,71 and it is considered
a clinical correlate of the wind-up phenomenon that is associated
with central sensitization.57,58 Pain inhibition can be assessed by
applying a noxious stimulus alone over a body site, then repeating
it concurrent with or after a second noxious stimulus is presented
on a distant body site. Such testing protocol is known as
conditioned pain modulation (CPM),95 and it is considered the
clinical equivalent of “pain inhibits pain” testing in animal models,
which triggers diffuse noxious inhibitory controls.45 Both TSP18,31
and CPM47 responses have been extensively investigated in
chronic pain patient samples and reported outcomes suggest
that abnormal EPM, ie, increased pain facilitation and/or impaired
pain inhibition, is present in those patients compared with pain-
free controls.
Endogenous pain modulation function has also been assessed
in chronic OFP conditions with conflicting results. Temporoman-
dibular disorder is the most studied condition, with early reports
suggesting impaired EPM in patients relative to controls.39,53,54
Some later studies supported these results,24,41 whereas others
did not find such impairments.21,81 This was also the case for
PDAP, where both normal5 and impaired64 CPM responses have
been reported. Burning mouth syndrome has been investigated
using diverse methods including neurophysiological and quan-
titative sensory testing,20,37 but little is known about EPM function
in this patient population. Taken together, these contradicting
results and lack of aggregate analysis of this literature prevent any
solid conclusion about EPM function in patients with
chronic OFP.
To address this gap in our knowledge about EPM function in
chronic OFP, we performed a systematic review of the literature
followed by a meta-analysis. Our aims were to: (1) summarize
qualitatively the available studies of EPM function assessed in
patients with OFP presenting with nonparoxysmal pain; and (2)
perform a quantitative synthesis of TSP and CPM responses in
patients with chronic OFP relative to pain-free controls.
2. Methods
We performed this systematic review and meta-analysis following
the Preferred Reporting Items for Systematic reviews and Meta-
Analyses (PRISMA) statement.48,61 The focus of this review was
defined on specific populations, interventions, comparison, and
Copyright Ó 2018 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
PAIN®
outcomes, ie, PICO elements, as endorsed by the Cochrane
Collaboration.32
2.1. Eligibility criteria
Inclusion criteria for the systematic review were developed using
a framework based on the following PICO components:
(1) Population (P): Adults ($18 years) who were either pain-free or
were rendered a diagnosis of TMD, PDAP, or BMS based on
published diagnostic criteria. Examples include the Research
Diagnostic Criteria for TMD,16 and diagnostic criteria based on
experts’ consensus for PDAP66,93 and BMS.27 Persistent
postendodontic pain, if present for .3 months, fits the criteria
for PDAP as defined here66 (see also search criteria in
supplementary Table S1, available online at http://links.lww.
com/PAIN/A578).
(2) Interventions (I): EPM testing for:
a) Pain facilitation: TSP as a psychophysical correlate of the
wind-up phenomenon reported from electrophysiological
studies in animal models57,58: suprathreshold noxious
stimuli repeated at frequency $0.33 Hz;
b) Pain inhibition: CPM as a psychophysical correlate of the
diffuse noxious inhibitory controls measured in animal
studies45: presentation of a noxious test stimulus alone,
then again concurrent (parallel) or right after (sequential)
a second noxious (conditioning) stimulus presented else-
where in the body;
(3) Comparison (C): Comparison between patients with OFP and
pain-free controls;
(4) Outcomes (O): Outcome measures for:
a) Temporal summation of pain: pain perception evoked by
the test stimulus when first presented and after several
repeated presentations. Examples include wind-up ratio,
difference of pain ratings between initial and last stimuli, and
slope of a regression line fitted for the first 5 pain ratings.
b) Conditioned pain modulation: pain perception evoked by
the test stimulus presented alone and again during or right
after presentation of the conditioning stimulus. Pain
perception could be determined using pain ratings, eg,
0 to 100 numerical rating scale, for a predefined stimulus
intensity or physical units for stimulus intensity, eg, kPa or
mA, for a predefined pain threshold.
There were no restrictions for language of publication or
publication date. Studies that did not include a pain-free control
group were excluded. In addition to the above criteria, included
studies also needed to report data for EPM testing outcome
measures (mean, SD, and sample sizes; or other data that
allowed those to be determined) for both patient and control
groups in order to be included in the quantitative analysis.
2.2. Search strategy
Literature searches were conducted by a trained librarian
(N.T.M.). Controlled vocabulary (MeSH terms) and keywords
search strategies were developed for MEDLINE (National Library
of Medicine, Bethesda, MD) through the Ovid interface (1946-
present, Epub Ahead of Print, In-Process & Other Non-Indexed
Citations, Ovid MEDLINE(R) Daily, Ovid MEDLINE and Versions
(R)) and translated to Embase (1947-2017 week 44, Elsevier,
Amsterdam, The Netherlands), and the Cochrane Central
Register of Controlled Trials, all on April 12, 2017. Supplementary
Table S1 (available online at http://links.lww.com/PAIN/A578)
describes the detailed search strategy. The search results were
imported from the different databases into EndNote X8 (Clarivate
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Analytics, Philadelphia, PA) for deduplication and reference
management. Subsequently, all references found were exported
to a spreadsheet with the following information: authors, year of
publication, article title, journal, volume, issue, and abstract. An
updated and final search was performed on October 24, 2017.
Additional searches using the reference lists of included studies
and reviews about EPM were performed to identify additional
potentially eligible studies.
2.3. References screening and eligibility assessment
All references identified were screened independently by 2 of the
authors (E.J.MF. and A.H.B.) based on the references’ titles and
abstracts. The 2 raters trained to apply the eligibility criteria using
20 randomly selected references, which were independently
reviewed by each rater who noted the reason(s) for exclusion.
Then, the raters met to compare their screening results, and
disagreements were discussed until a consensus was reached
based on the specified eligibility criteria described above. If any
disagreement remained after the meeting, arbitration by clinical
researchers experienced in meta-analyses from the University of
Minnesota School of Dentistry was sought and deemed final.
Subsequently, a calibration procedure took place with additional
50 randomly selected references. Interrater agreement was
calculated using a prevalence-adjusted, bias-adjusted (PABA)
kappa,8 resulting in “almost perfect” agreement (PABA kappa 5
0.96) according to proposed guidelines for kappa
interpretation.44
Remaining references (53629) were then screened by both
raters, also with “almost perfect” interrater agreement (PABA
kappa 5 0.98). References with insufficient information in the title
and abstract for eligibility assessment had full text retrieved and
reviewed by both raters. The same process as during training and
calibration was used to arrive at a consensus on which articles
met inclusion criteria for systematic review and for meta-analysis.
2.4. Data extraction and study variables
Full text of all articles that met inclusion criteria was acquired in
electronic format. Data extraction was performed by one reviewer
(E.J.MF.) using standardized forms, which was later indepen-
dently checked by the second reviewer (A.H.B.), and disagree-
ments were resolved through reconciliation and consensus. Data
extracted for the systematic review included: number of patients
with OFP and controls, number of females and males in each
group, mean age, pain duration, test stimulus type (electrical,
noxious heat, pinprick, and pressure), test stimulus location
(trigeminal or nontrigeminal), group design relative to effect size
calculation (2 independent groups, pretest-posttest-control), and
results of statistical testing of between-group comparisons for the
outcome measure(s).
For meta-analysis, we collected descriptive data needed to
calculate effect sizes in the form of standardized mean differ-
ences (mean values, SDs, and sample sizes). One issue in
gathering these data is that it can be reported in different ways.
For example, many studies reported EPM outcome measures for
each group (patients and controls) as ratio of the test stimulus
pain ratings when presented with the conditioning stimulus (for
CPM) or after repeated presentation (for TSP) relative to pain
ratings for initial presentation of the test stimulus alone (2
independent group design [2indgrp]). Alternatively, those out-
comes were sometimes reported as 2 mean values per group:
mean pain rating for the initial presentation of the test stimulus
and another mean rating during CS (CPM) or repeated
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www.painjournalonline.com 1443
presentation (TSP) (pretest-posttest-control design [pptc]). All
data available from each study were included, which for some
studies meant including the same outcome measure reported in
both ways (2indgrp and pptc). Another issue found was outcome
measures that were reported as median and range, requiring
conversion to mean and SD using published guidelines.35 When
data needed for effect size calculation were not available in the
published article and/or supplementary files, it was requested
from the study’s authors, with 2 contact attempts 1 month apart.
2.5. Assessment of risk of bias
Risk of bias was assessed independently by both reviewers (E.J.
MF. and A.H.B.) using criteria developed for a meta-analysis of
CPM in chronic pain.47 In brief, 4 categories were considered
according to the following criteria: (1) whether the study personnel
assessing outcome measures were blinded to participant group
assignment; (2) whether cases were representative of the
population, assessed through use of internationally recognized
criteria and clear description of sources of patient population
samples recruited; (3) whether cases and controls were
comparable for age and sex; and (4) whether the analysis
controlled for known confounders of sensory testing, ie,
medication/caffeine intake before EPM testing, clinical pain
present on test day, time of day when testing was performed,
phase of menstrual cycle (for females), and screening for
participants with conditions known to influence sensory testing
(other chronic pain conditions, diabetic neuropathy, etc.).
All studies included in the systematic review were assessed for
each of these categories and were classified as low (50),
moderate (51), or high risk (52).47 For each study, the sum of the
4 category scores represents the total risk of bias, ranging from
0 (low risk) to 8 (high risk).
2.6. Data synthesis and analysis
All analyses were implemented using the R system (v.3.4.2)73 and
the packages “metafor” (v2.0.0),90 “robumeta” (v2.0),19 and
“weightr” (v1.1.2).11 P values ,0.05 were considered significant.
Effect size(s) for each individual study were calculated as the
standardized mean difference using the “escalc” function
(“metafor” package). For the 2 independent groups design, effect
sizes were computed as Hedges’s g28; for the pretest-posttest-
control design, we estimated standardized effect sizes using
pooled pretest SD.62 These calculations were done in a way that
positive effect sizes represented increased TSP/impaired CPM in
the patient group relative to pain-free controls, whereas negative
effect sizes meant nonincreased TSP/nonimpaired CPM.
To address the issue of multiple effect sizes reported by
individual studies, 2 meta-analytical approaches were used.
Traditional meta-analysis was performed by averaging all
effect sizes for a given EPM test (TSP or CPM) reported by
a single study. Thus, in this approach, each study contributed
only 1 effect size per EPM test, satisfying the assumption of
independence of estimated effect sizes. Then, a random-
effects model was fitted using the restricted maximum-
likelihood estimator through the “rma” function (“metafor”
package), as this model has been shown to be efficient and
approximately unbiased.89 Heterogeneity was assessed using
2 methods33:
(1) Cochran Q-test, where a P value ,0.05 denotes statistically
significant heterogeneity between studies;
(2) I2 statistic, the percent of total variability in effect size estimate
due to heterogeneity rather than chance. Values of I2 were
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E.J. Moana-Filho et al. 159 (2018) 1441–1455
Figure 1. PRISMA flow chart. EPM, endogenous pain modulation.
assessed as low (525%), medium (550%), and large (575%)
heterogeneity, respectively (Del Re, 2015).
The second meta-analytic approach used was robust variance
estimation (RVE), a recently proposed method that allows for
synthesis of dependent effect sizes when no information on their
covariance structure is available.29 This way, within-study effect
size dependencies are handled while avoiding loss of information
due to averaging. Robust variance estimation meta-analysis for
each EPM test was implemented using the “robu” function from
the “robumeta” package, using the default within-study effect
size correlation (Rho 5 0.8) and adjustment for small samples86 to
fit the meta-regression models.
Sensitivity analyses explored influence of different factors on
the TSP and CPM overall effect size estimates. For traditional
meta-analysis, we examined: (1) impact of the random-effect
model used, by recalculating the overall estimates using 7
additional estimators available through the “rma” function
(Hunter–Schmidt, Hedges, DerSimonian–Laird, Sidik–Jonkman,
Maximum-likelihood, Empirical Bayes, and generalized Q-
statistic [GENQ]); and (2) “Leave-one-out” analysis, to assess
whether removing any individual study from the meta-analysis
would influence the overall estimates. For RVE meta-analysis, we
performed a sensitivity analysis to determine how different values
of within-study correlation (Rho values from 0 to 1, in 0.2 steps)
influence the overall estimates.
Meta-regression using moderators that could potentially
account for effect size heterogeneity was performed for
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traditional meta-analysis: mean age (,40 years and .40
years) and sex of participants (female and mixed) as well as
OFP condition (TMD, PDAP, and BMS). In addition to these
moderators, for RVE meta-analysis we also investigated the
influence of test stimulus location (trigeminal or
nontrigeminal), test stimulus type (electrical, pinprick,
pressure, or noxious heat), and effect size study design (2
independent groups, pretest-posttest-control). The Q-test
was performed, where the component “Q model ” represents
the dispersion of effect sizes explained by the moderator(s)
assessed. A statistically significant (P , 0.05) “Q model ”
suggests that the moderators influence the overall effect size
estimate.
Finally, we used diagnostic measures to identify studies
that could be potential outliers and “influential cases.”90,91
These measures include: externally standardized residuals,
DFFITS values, Cook’s distances, covariance ratios, esti-
mates of tau2, and test statistics for (residual) heterogeneity
(Q E) when each study is removed in turn, diagonal elements of
the hat matrix and the weights (in %) given to the observed
outcomes during the model fitting. These are equivalent to
outlier and case diagnostics for standard regression models,
adapted to meta-analysis by considering both sampling
variability and between-study heterogeneity. Large relative
changes in the various measures for an individual study when
compared with the others warrant closer examination of its
characteristics.91
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Table 1
Descriptive characteristics for studies of temporal summation of pain (TSP).
Study Population Sex Sample size: N Mean Mean pain Test Test Patients outcome Patients outcome Risk of
patients; N age duration in stimulus stimulus relative to relative to bias
controls, (% (y) years (SD) type location controls, controls, (0-8)
female) trigeminal nontrigeminal
Studies
included in the
meta-analysis
Maixner TMD Female 23 (100) ,40 4.6 (4.5) Noxious Nontrigeminal — Nonincreased 4
et al.54 heat
24 (100)
Sarlani TMD Female 25 (100) ,40 4 (5.1) Pressure Nontrigeminal — Increased 3
et al.79 25 (100)
Baad- PDAP Mixed 10 (70.0) .40 8.8 (14.2) Pinprick Trigeminal Nonincreased — 5
Hansen 10 (60.0)
et al.3
Greenspan TMD Mixed 185 (83.8) * * Pinprick Nontrigeminal — Increased (pinprick) 6
et al.24 and and nonincreased
noxious (noxious heat)
heat
1633 (56.6)
Ribeiro- TMD Mixed 49 (65.3) ,40 3.5 (2.6) Noxious Nontrigeminal — Nonincreased 5
Dasilva heat
et al.75 70 (47.1)
Sato et al.81 TMD Female 13 (100) ,40 * Noxious Both Nonincreased Nonincreased 3
heat
20 (100)
Baad- PDAP Mixed 47 (85.1) .40 1.5-20 (only Pinprick Both * Nonincreased 4
Hansen range
et al.6 reported)
69 (76.8)
Chen et al.9 TMD Female 159 (100) ,40 9.5 (8.3) Noxious Nontrigeminal — Increased 5
heat
131 (100)
Garret TMD Female 30 (100) ,40 8.2 (10.1) Pressure Nontrigeminal — Nonincreased 4
et al.21 30 (100)
Kothari TMD Mixed 34 (79.4) ,40 * Pinprick Trigeminal * — 4
et al.43 34 (73.5)
Nasri-Heir PDAP Mixed 27 (74.1) .40 * Pinprick Both Nonincreased Nonincreased 4
et al.64 27 (74.1)
Porporatti PDAP Mixed 25 (76.0) .40 3.5 (2.6) Pinprick Trigeminal Nonincreased — 4
et al.69 25 (76.0)
Gil-Martinez TMD Female 19 (100) .40 * Pinprick Both Increased Increased 4
et al.23 20 (100)
Hilgenberg- TMD Female 20 (100) .40 * Pinprick Both Nonincreased Increased 2
Sydney 20 (100)
et al.34
Janal TMD Female 125 (100) ,40 8.9 (8.3) Noxious Nontrigeminal — Nonincreased 4
et al.38 heat
43 (100)
Kothari TMD Mixed 58 (82.8) ,40 * Pinprick Trigeminal Nonincreased — 5
et al.42 41 (73.2)
Yang et al.94 TMD Mixed 40 (80.0) .40 14.5 (21.1) Pinprick Both * * 4
70 (51.4)
Hartmann BMS Mixed 5 (80.0) .40 1.9* Pinprick Both Nonincreased * 6
et al.26 8 (100)
Studies not
included in the
meta-analysis
Sarlani TMD Mixed 43 (62.8) ,40 * Pressure Nontrigeminal — Increased —
et al.78 (controls 20 (0.0)
just
males)
Pfau et al.68 TMD Mixed 23 (87.0) .40 * Pinprick Both Nonincreased Nonincreased —
18 (83.3)
(continued on next page)

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E.J. Moana-Filho et al. 159 (2018) 1441–1455
Study Population Sex Sample size: N
patients; N
controls, (%
female)
Raphael TMD Female 19 (100)
et al.74
17 (100)
Porporatti PDAP Mixed 20 (75.5)
et al.70 20 (70.0)
* Not reported.
BMS, burning mouth syndrome; PDAP, persistent dentoalveolar pain disorder; TMD, temporomandibular disorder.
2.7. Assessment of publication bias
Publication bias can exert substantial influence on a meta-
analysis, so we used several approaches to estimate and, when
present, correct for it. First, we determined Rosenthal’s fail-safe N
(“file drawer analysis”) that estimates the number of unpublished
studies that would need to exist to turn a significant overall effect
size estimate into a nonsignificant one.77 Second, we visually
assessed symmetry in funnel plots, which plotted studies’ effect
sizes against their respective standard errors. To formally test for
publication bias, we first conducted a regression model using
effect sizes and their standard errors that detect funnel plot
asymmetry by assessing the distance of the intercept from the
origin,17 then a rank correlation test between effect size estimates
and their variances, where publication bias is represented by
a significant correlation.7 Finally, if publication bias was present,
we corrected for it using 2 methods: (1) trim and fill,15
a nonparametric technique that estimates the number of missing
studies in a meta-analysis and gives a corrected overall effect size
estimate. This correction is performed by removing the most
extreme results from 1 side of the funnel plot, then “filling” those
by adding simulated small effect sizes in an iterative fashion; (2)
weight function models for publication bias,88 which represent
the process by which some studies are more likely to be
published than others based on some characteristics, eg,
statistical significance. “One-tailed” models represent publication
bias favoring studies reporting significantly increased TSP and/or
impaired CPM responses for patients with OFP relative to pain-
free controls, whereas “2-tailed” bias would favor publication of
studies reporting significant effects in either direction (increased/
nonincreased TSP and/or impaired/nonimpaired CPM). The
“weightr” package was used to implement this analysis using 4
weight functions88: moderate 1-tailed selection, severe 1-tailed
selection, moderate 2-tailed selection, and severe 2-tailed
selection.
2.8. Supplementary analysis for specific orofacial
pain conditions
For each OFP condition and EPM test that had effect sizes
calculated from 3 or more studies, we performed a traditional
meta-analysis to present results specific to the patient population
and EPM test reported, as readers may be interested in more
granular results.
3. Results
After reference screening and full-text eligibility assessment, 26
published studies were included for qualitative synthesis (Fig. 1).
Both raters were able to reach consensus on all disagreements
that arose during screening and full-text assessment; thus, there
was no need to escalate it to arbitration by others.
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Table 1 (continued)
Mean Mean pain Test Test Patients outcome Patients outcome Risk of
age duration in stimulus stimulus relative to relative to bias
(y) years (SD) type location controls, controls, (0-8)
trigeminal nontrigeminal
,40 1* Noxious Both Nonincreased Nonincreased —
heat
.40 * Pinprick Trigeminal Nonincreased — —
Twelve studies did not report sufficient data to meet the
inclusion criteria for the quantitative synthesis, ie, meta-
analysis. Authors of those studies were contacted through
email on 2 occasions 1 month apart, and replies were
received for 8 studies but not for the other 4 studies, leading
to their exclusion from the quantitative synthesis. 68,70,74,78
Thus, 22 published studies were included in the meta-
analysis (Fig. 1). Descriptive characteristics of all studies
included are summarized in Tables 1 and 2 for TSP and CPM,
respectively.
3.1. Characteristics of the study population
The focus here is on the population samples from the 22
studies included in the meta-analysis since these studies
were used to calculate the overall effect size estimates for
TSP and CPM. Eight hundred ninety-four patients with OFP
(89.3% females) and 2300 pain-free controls (63.8% females)
were included in studies reporting TSP outcome measures,
whereas studies reporting CPM outcomes included 257
patients with OFP (86.8% females) and 243 pain-free controls
(84.4% females). A single study reporting TSP outcomes
contributed 1818 participants (185 patients and 1633
controls).24 Twelve studies reported that the mean age of
their samples was younger than 40 years (1 study did not
report group-specific mean age). Mean pain duration
reported for patients with OFP was $1.5 year (max 5 14.5
years); 9 of the 22 studies did not report this descriptor
(Tables 1 and 2).
3.2. Qualitative synthesis (systematic review)
Of the studies included in the systematic review (k 5 26), 22
reported TSP outcomes in patients with TMD (k 5 16), PDAP
(k 5 5), or BMS (k 5 1) (Table 1). The most frequently used
test stimulus was pinprick (k 5 13), followed by noxious heat
(k 5 7) and pressure (k 5 3). Test stimulus body location
included trigeminally innervated sites in 5 studies, non-
trigeminal in 8, and both trigeminal and nontrigeminal in 9
studies. Only 1 study found TSP to be increased within the
trigeminal territory, whereas 6 studies reported TSP in-
creased in nontrigeminal body sites. Risk of bias for TSP
studies included in meta-analysis ranged between 2 and 6,
with a median of 4.
Conditioned pain modulation outcomes were reported in 9
studies (Table 2), with 7 including patients with TMD. The most
frequent test stimulus type used was pressure (k 5 5), and half the
studies (k 5 5) tested both trigeminal and nontrigeminal body
sites with 3 studies reporting impaired CPM in both locations.
Risk of bias in CPM studies had similar distribution as those for
TSP (median 5 4).
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Table 2

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Number 8
Descriptive characteristics for studies of conditioned pain modulation (CPM).
Study Population Sex Sample size: N patients; Mean Mean pain Test Test Conditioning Conditioning Patients outcome Patients outcome Risk of
N controls, (% female) age (y) duration in years stimulus stimulus stimulus type stimulus relative to controls, relative to controls, bias (0-
(SD) type location location trigeminal nontrigeminal 8)
Studies included
in the meta-
analysis
Kashima TMD Female 20 (100) ,40 * Pressure Nontrigeminal Cuff pressure Nontrigeminal — Impaired 6
et al.39 20 (100)
Baad-Hansen PDAP Mixed 38 (78.9) .40 7.3 (3.2) Electrical Trigeminal Capsaicin Trigeminal Nonimpaired — 4
et al.5 27 (66.7)
King et al.41 TMD Female 14 (100) ,40 * Noxious Nontrigeminal Cold-water bath Nontrigeminal — * 4
heat
28 (100)
Garret et al.21 TMD Female 30 (100) ,40 8.2 (10.1) Pressure Nontrigeminal Cold-water bath Nontrigeminal — Nonimpaired 4
30 (100)
Oono et al.67 TMD Mixed 16 (87.5) Patients 6.3 (7.1) Pressure Both Pericranial Trigeminal Impaired Impaired 4
.40 pressure
16 (87.5) Controls
,40
Kothari et al.43 TMD Mixed 34 (79.4) ,40 * Pressure Both Cold-water bath Nontrigeminal Nonimpaired Nonimpaired 4
34 (73.5)
Nasri-Heir PDAP Mixed 27 (74.1) .40 * Pinprick Both Hot-water bath Nontrigeminal Impaired Impaired 4
et al.64 27 (74.1)
Hilgenberg- TMD Female 20 (100) .40 * Pinprick Both Hot-water bath Nontrigeminal Impaired Impaired 2
Sydney 20 (100)

www.painjournalonline.com
et al.34
Kothari et al.42 TMD Mixed 58 (82.8) ,40 * Pressure Both Cold-water bath Nontrigeminal Impaired Nonimpaired 5
41 (73.2)
* Not reported.
PDAP, persistent dentoalveolar pain disorder; TMD, temporomandibular disorder.

1447
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 1448
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E.J. Moana-Filho et al. 159 (2018) 1441–1455
Figure 2. Traditional meta-analysis forest plots for: (A) temporal summation of pain; and (B) conditioned pain modulation. CPM, conditioned pain modulation; RE,
random effect; TSP, temporal summation of pain.
3.3. Quantitative synthesis (meta-analysis)
3.3.1. Traditional meta-analysis
Twenty-seven effect sizes (18 for TSP and 9 for CPM) were
computed from the 22 studies included in the meta-analysis (some
studies reported effect sizes for both EPM tests). Those effect sizes
were calculated mostly from TMD studies (TSP 5 13 and CPM 5 7),
whereas PDAP (TSP 5 4 and CPM 5 2) and BMS (TSP 5 1 and
CPM 5 0) contributed with substantially fewer effect sizes.
3.3.1.1. Temporal summation of pain
The overall standardized effect size estimate for TSP was 0.30 (95%
confidence interval [CI]: 0.11-0.49; P 5 0.002), which is considered
a “small” to “medium” effect size per Cohen’s convention12 and
suggests that TSP is increased in patients with OFP relative to pain-
free controls. Figure 2A shows individual study effect sizes for TSP
and their respective 95% CIs; most studies’ 95% CIs include the
overall estimate with exception of Nasri-Heir et al.64 and Sarlani
et al.79 Medium to large heterogeneity across studies was found
Copyright Ó 2018 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
PAIN®
(Q [df 5 17] 5 41.8, P 5 0.001; I2 5 70.2% [95% CI: 44.3%-90.9%]).
Sensitivity analyses showed that the different estimators for random-
effect models had minimal impact in the overall estimate (min 5 0.26,
max 5 0.31, all P values ,0.01), as did the “leave-one-out” analysis
(min 5 0.23, max 5 0.33, all P values ,0.006). These results also
support increased TSP in patients with OFP. Meta-regression found
that only sex of participants influenced the overall effect size estimate
(Qmodel [df 5 1] 5 4.01; P 5 0.045), with studies including only females
(k 5 8) showing a “medium” effect size (50.51, P , 0.001), whereas
those including mixed sexes (k 5 10) showed an “small” effect size
estimate (50.14, P 5 0.248). Mean age (P 5 0.452) and OFP
condition (P 5 0.144) were not statistically significant moderators.
The study by Sarlani et al.79 was deemed an “influential case”
among TSP studies (supplementary Fig. S1A, available online at
http://links.lww.com/PAIN/A578). After excluding this study
from the meta-analysis, the overall estimate for TSP was 0.23
(95% CI: 0.14-0.33; P , 0.001), with virtually no heterogeneity
between the remaining studies (Q [df 5 16] 5 20.3, P 5 0.206;
I2 5 0.01% [95% CI: 0.01%-77.6%]).
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Figure 3. Robust variance estimation meta-analysis forest plot for temporal summation of pain.

3.3.1.2. Conditioned pain modulation
For CPM, the overall effect size estimate was large but did not
reach statistical significance (standardized estimate 5 1.36; 95%
CI: 20.09 to 2.81; P 5 0.066), whereas very large heterogeneity
across studies was present (Q [df 5 8] 5 108.3, P , 0.001; I2 5
98.0% [95% CI: 95.6%-99.5%]) (Fig. 2B). The choice of random-
effect model affected the overall estimate: 2 of the 7 estimators
gave a significant overall effect size estimate (DerSimonian–Laird
estimate 5 1.18 [95% CI: 0.43-1.94; P 5 0.002]; Hunter–
Schmidt estimate 5 1.15 [95% CI: 0.45-1.86; P 5 0.001]).

Copyright Ó 2018 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
 1450
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E.J. Moana-Filho et al. 159 (2018) 1441–1455
Figure 4. Robust variance estimation meta-analysis forest plot for conditioned pain modulation.
“Leave-one-out” analysis showed that when the study by King
et al.41 was removed, the estimate became significant (estimate
5 0.66, 95% CI: 0.07-1.24; P 5 0.028). Meta-regression did not
find statistically significant influences on the CPM overall estimate
for mean age (P 5 0.800), sex (P 5 0.465), or OFP condition (P 5
0.898), suggesting that the substantial heterogeneity found was
not accounted for by any of these moderators.
King et al.41 study was identified as an “influential case” among
studies reporting CPM outcomes (supplementary Fig. S1B, available
online at http://links.lww.com/PAIN/A578). Removing this study
from the meta-analysis led to a statistically significant overall estimate
as mentioned above for the “leave-one-out” analysis, although large
heterogeneity was still present for the remaining 8 studies (Q [df 5 7]
5 47.3, P , 0.001; I2 5 87.9% [95% CI: 71.6%-97.2%]).
3.3.2. Robust variance estimation meta-analysis
Robust variance estimation allows all effect sizes within each
individual study to be included, giving a total of 72 effect sizes (44
Copyright Ó 2018 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
PAIN®
for TSP and 28 for CPM). As for the traditional approach, they
were mostly estimated from TMD studies (TSP 5 27 and CPM 5
21) with fewer from PDAP (TSP 5 15 and CPM 5 7) and BMS
(TSP 5 2 and CPM 5 0) studies.
The RVE overall effect size estimate for TSP was 0.30 (95% CI:
0.09-0.50; P 5 0.007), again suggesting that patients with OFP
present with increased TSP relative to pain-free controls. For
CPM, a large overall estimate (51.19; 95% CI: 20.20 to 2.58) that
again did not reach significance (P 5 0.084) was found. Figures 3
and 4 (TSP and CPM) show all effect sizes and respective 95%
CIs for each study. Sensitivity analysis for RVE showed that
varying the within-study correlation did not change TSP and CPM
overall estimates to the second decimal place.
None of the moderators tested for RVE meta-regression were
deemed statistically significant for TSP (mean age: P 5 0.450;
sex: P 5 0.085; OFP condition: P 5 0.847; test stimulus site: P 5
0.272; test stimulus type: P . 0.303; and effect size study design:
P 5 0.810) or CPM (mean age: P 5 0.920; sex: P 5 0.590; OFP
condition: P 5 0.969; test stimulus location: P 5 0.517; test
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Figure 5. Funnel plots of studies reporting outcomes for: (A) temporal
summation of pain; and (B) conditioned pain modulation.
stimulus type: P . 0.181; and effect size study design: P 5
0.815).
3.4. Assessment of publication bias
Fail-safe N calculation, ie, “file drawer analysis,” showed that 177
hypothetical studies reporting no between-group differences for
TSP outcomes would need to be added to the meta-analysis to
deem the overall estimate not significant. Because the CPM
overall estimate was not statistically significant, this analysis was
not performed for it.
Visual analysis of the funnel plot for TSP studies showed
a reasonably symmetrical graph (Fig. 5A), indicating a low
likelihood for publication bias. This was confirmed through formal
assessment using regression (t(16) 5 0.66, P 5 0.519) and rank
correlation (Kendall’s tau 5 0.22, P 5 0.229) tests. Because no
publication bias for TSP studies was present, no correction for it
was done.
The funnel plot for CPM studies suggested publication bias
given its substantial asymmetry determined both by visual
inspection (Fig. 5B) and quantitatively (the regression test: t(7)
5 4.70, P 5 0.002; the rank correlation test: Kendall’s tau 5 0.67,
P 5 0.013). Publication bias correction using the “trim and fill”
method did not change the CPM overall effect size estimate
(corrected estimate 5 1.36); however, it changed substantially for
the “one-tailed” selection bias models (corrected estimate using:
moderate 1-tailed selection 5 0.83; severe 1-tailed selection 5
20.58; moderate 2-tailed selection 5 1.28; and severe 2-tailed
selection 5 1.21). This means that presence of publication bias
Copyright Ó 2018 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
www.painjournalonline.com 1451
favoring studies that reported impaired CPM in patients with OFP
substantially alters the overall estimate, and even reverses that
original conclusion for severe 1-tailed selection bias. Taken
together, these results suggest that the CPM overall estimate is
not robust and most likely is influenced by publication bias.
To assess the impact of the influential CPM study,41
publication bias analyses were rerun without it. Both tests for
funnel plot asymmetry became nonsignificant (the regression
test: t(6) 5 2.39, P 5 0.054; the rank correlation test: Kendall’s
tau 5 0.50, P 5 0.109). “Trim and fill” correction led to no
changes to the overall estimate when excluding the influential
CPM study. Both “one-tailed” selection bias models still showed
substantially different corrected overall estimates compared with
the overall estimate without the influential study (50.66),
suggesting that the influential study does not fully account for
the putative publication bias of CPM studies (moderate 1-tailed
selection 5 0.47; severe 1-tailed selection 5 0.02; moderate 2-
tailed selection 5 0.59; and severe 2-tailed selection 5 0.53).
3.5. Supplementary analysis for specific orofacial
pain conditions
Traditional meta-analysis of TSP studies including only patients
with TMD (k 5 13) found a small to medium effect size (estimate 5
0.39; 95% CI: 0.18-0.60; P , 0.001), suggesting that patients
with TMD present pain facilitation relative to pain-free controls as
measured through TSP testing (supplementary Fig. S2A, avail-
able online at http://links.lww.com/PAIN/A578). By contrast,
meta-analysis of studies reporting CPM responses in patients
with TMD (k 5 7) showed a large overall effect size estimate (5
1.44; 95% CI: 20.44 to 3.31) that did not reach statistical
significance (P 5 0.133) (supplementary Fig. S2B, available online
at http://links.lww.com/PAIN/A578).
Studies reporting EPM outcomes for patients with PDAP did
not show statistically significant differences relative to controls for
TSP (estimate 5 20.06; 95% CI: 20.41 to 0.28; P 5 0.720)
(supplementary Fig. S3, available online at http://links.lww.com/
PAIN/A578). No meta-analysis for CPM in PDAP or BMS was
performed because only 2 studies of CPM testing in patients with
PDAP and 1 study testing TSP in patients with BMS were
included, respectively.
4. Discussion
This is the first meta-analysis focused on EPM function in patients
suffering from chronic nonparoxysmal OFP conditions. The
results suggest that increased pain facilitation is present in
patients with OFP relative to pain-free participants. A trend for
pain inhibition impairment in patients was observed, but the
overall effect size estimate was not robust, as shown by both
sensitivity and publication bias analyses of CPM studies.
Comprehensive meta-analytic approaches were used to arrive
at these results using specific models for effect size study design
used (2 independent groups, pretest-posttest-control), and 2
meta-analytical methods: traditional meta-analysis and a novel
method to account for within-study multiple effect sizes and their
covariance, RVE. All together, these results suggest that EPM
dysfunction is one of several putative CNS mechanisms involved
in OFP clinical presentation.
Increased pain facilitation, as measured by TSP, is present in
patients with OFP relative to pain-free controls, given the highly
significant overall effect size estimate and that sensitivity analyses
did not reduce that estimate to nonsignificance. Variability of
effect sizes between individual studies (heterogeneity) was
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E.J. Moana-Filho et al. 159 (2018) 1441–1455
relatively large but this was mostly driven by 1 influential study,79
that once removed from meta-analysis all but eliminated
heterogeneity. Meta-regression showed that participant sex
was a significant moderator for TSP, with females presenting
greater TSP facilitation relative to studies reporting data from
mixed sexes. Despite this robust overall effect estimate for
increased TSP in patients with OFP, its small to medium size
suggests that increased pain facilitation in patients with OFP may
have a moderate role on symptom manifestation, ie, clinical pain.
On the other hand, impairment of pain inhibition assessed
using CPM testing was represented by a large overall effect size
estimate that showed a trend toward but did not reach statistical
significance. However, different analyses showed that this
estimate is not robust. First, sensitivity analysis showed that the
choice of random-effects model had a great influence, and if one
of the most commonly used models14 was chosen, CPM would
be deemed significantly impaired in patients with OFP relative to
controls. Second, removing from the meta-analysis the study
with the biggest individual effect size41 both reduced and made
significant the overall estimate. Third, publication bias analyses
showed that it is most likely present for CPM studies in patients
with OFP. Finally, heterogeneity across studies was large
(.86.7%) and was not reduced by removal of the influential
study.41 It is known that several factors can influence CPM
responses including testing protocols and clinical
characteristics,30,40,47 and this may explain in part the large
heterogeneity reported here. An alternative explanation is that
factors still unknown influence pain inhibition assessment through
CPM testing. Based on results from published studies, it seems
that currently it is not possible to unambiguously state that
impaired pain inhibition is present or absent in patients with OFP.
We performed a comprehensive systematic review of the
literature with no language restrictions, resulting in 3699
references screened and 26 studies meeting our inclusion
criteria. Despite this approach, some often cited studies about
EPM function in patients with OFP were not included. Reasons
for excluding these studies were that they used an EPM testing
protocol that did not fit our inclusion criteria,53,92 whereas other
studies were included in the systematic review but not in meta-
analysis because the data reported were not in sufficient detail
for calculation of a standardized mean difference.68,70,74,78
Aggregating results from individual studies into an overall effect
size estimate poses several challenges. First, some studies
reported EPM outcomes as a single mean relative change per
group (2 independent group) and/or as 2 mean values per group
(pretest-posttest-control), demanding different effect sizes
calculation formulas.28,62 Second, most studies reported
multiple outcome measures, which leads to interdependent
effect size estimates. Several methods have been suggested to
deal with this problem,60 and 2 methods were applied here: (1)
averaging of all effect sizes in a given study (traditional meta-
analysis); and (2) RVE, which accounts for statistical de-
pendencies between a study’s multiple estimated effect sizes.29
Both methods gave similar overall effect size estimates for TSP
and CPM. Finally, overall effect size estimates can be unduly
biased by influential cases, ie, studies with results that are
outlying relative to other included studies. Once influential
studies for this meta-analysis were identified, their removal
caused: (1) substantial reduction of heterogeneity for TSP, and
(2) the CPM overall estimate to become significant. These steps
highlight the complexity of performing meta-analysis of EPM
studies, as the data reported may be acquired using different
experimental methods and outcomes described in several valid
but different ways.
Copyright Ó 2018 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
PAIN®
Abnormal EPM is considered a shared mechanism across
chronic pain conditions,83 and a recent meta-analysis supported
this view by demonstrating pain inhibition impairment in patients
suffering from diverse chronic pain conditions including TMD.47
Endogenous pain modulation function in patients with chronic
pain is usually contrasted to that of pain-free participants using
inferential statistical testing, and if group differences meet the
established significance threshold, then EPM is deemed abnor-
mal. Tables 1 and 2 show that this approach has led to mixed
results being reported from the studies included in the systematic
review, making it difficult to ascertain whether abnormal EPM is
present in patients with OFP. Confounders for EPM testing are
numerous, such as those related to the experimental pro-
tocol72,87 and participant characteristics.30,63 For example, it
has been suggested that age, sex, menstrual cycle phase,
psychosocial factors, intake of caffeine and pharmacological
substances, and the time of day of testing may influence CPM
responses.47 Few studies included in the meta-analysis reported
controlling for these confounders during the day of testing, such
as the menstrual cycle phase21,34,79 and pain medications or
caffeine,34,41,68,75 which is reflected in the risk of bias scores
reported in Tables 1 and 2.
An alternative explanation for the conflicting results is that
individuals can express EPM in more than one way, depending on
the EPM experimental protocol used. For instance, the OPPERA
study found increased TSP in patients with OFP relative to
controls with repeated pinprick on the fingers but not using
noxious heat on the forearm.24 For the studies included in this
meta-analysis, pinprick (12 studies) and noxious heat (5 studies)
were the most commonly used test stimuli for TSP, whereas for
CPM, pressure stimuli (5 studies) and thermal water bath (4 cold
and 2 hot) were mostly used as test and conditioning stimuli,
respectively. Different test stimuli could explain at least some of
the variability in EPM testing outcomes; reliability for CPM testing
has been shown to depend on test and conditioning stimuli and
stimulation parameters, body sites used for testing, and the study
population sampled.40
Another aspect of EPM testing in patients with OFP relatively
understudied is differential responses when testing trigeminal and
nontrigeminal body sites. Recently, it was shown that in pain-free
controls, trigeminal sites may express weaker CPM responses
relative to nontrigeminal sites, whereas no differences were found
for TSP.46 Some studies that tested both sites in our meta-
analysis reported opposite results for trigeminal and nontrigemi-
nal sites for TSP34 and CPM42 for between-group comparisons,
although the majority found similar TSP23,64,81 and CPM34,43,64,67
responses for both trigeminal and nontrigeminal sites. Interest-
ingly, 1 study found that patients with TMD showed impaired
CPM in trigeminal sites but not in the forearm,67 suggesting
a regional CPM deficiency in these patients. Our meta-regression
did not support differences between trigeminal and nontrigeminal
test sites for TSP or CPM testing. Taken together, these results
raise the possibility that in some specific cases, EPM function
may be expressed in a regional fashion for some individuals that
could lead to a more localized expression of pain symptoms.
Future studies designed to specifically test this hypothesis are
needed to clarify whether regional EPM dysfunction, affecting
only trigeminally innervated territory, is present in patients with
chronic OFP.
A related issue is the paucity of data reporting normal TSP and
CPM responses in healthy, pain-free participants.40 One study76
that performed a battery of quantitative sensory testing on 180
healthy participants reported TSP using pinprick stimuli over the
face, hand, and feet, and the OPPERA case–control study24
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assessed TSP using both pinprick on fingers and noxious heat on
the forearm in a large sample of pain-free controls (n 5 1633) and
also of patients with chronic TMD (n 5 185). Conditioned pain
modulation responses were determined in large samples of pain-
free participants in 2 separate studies using cold-water hand bath
as the conditioning stimulus, 1 with a sample size of 125 that used
pressure pain thresholds over the forearm as the test stimulus,51
whereas the other used pressure pain thresholds over the
trapezius muscle and anterior tibialis in a sample of 1974
individuals.82 These studies provide initial data describing
a “normal” EPM function; however, further investigation into
additional aspects of EPM testing such as influence of
experimental protocol used and putative confounders is
warranted.
This systematic review and meta-analysis has some limita-
tions. The OFP conditions included in the present systematic
review and meta-analysis (TMD, PDAP, and BMS) were those
that present clinically as nonparoxysmal pain and/or dysesthesia
over orofacial tissues, are considered idiopathic in nature as other
overlapping chronic pain conditions.1,55,96 This eligibility criterion
excluded studies of populations suffering from other head and
facial pain conditions such as headaches in general and
trigeminal neuralgia. Headaches encompasses several different
clinical entities with diverse suggested pathophysiology,27
whereas trigeminal neuralgia pain is paroxysmal for which
peripheral etiological mechanisms were suggested.52 In addition,
the Cochrane Handbook suggests that the criteria for defining the
populations included in studies “should be sufficiently broad to
encompass the likely diversity of studies, but sufficiently narrow to
ensure that a meaningful answer can be obtained when studies
are considered in aggregate.”32 Given these suggested criteria,
TMD, PDAP, and BMS are chronic nonparoxysmal OFP
conditions that are most likely to share CNS mechanisms.
Conversely, this assumption is not readily applicable to other OFP
pain conditions affecting the head and face such as headaches in
general and trigeminal neuralgia—therefore, our results are not
generalizable to these patient populations. Another aspect is that
TMD is the most studied OFP condition for EPM, so studies
including this patient population are more numerous and this
influenced the overall effect size estimates reported for TSP and
CPM. To address this limitation of availability of published studies
on EPM in chronic nonparoxysmal OFP conditions, we performed
supplementary meta-analyses that considered studies that
focused on TMD and PDAP populations specifically (BMS only
had 1 study included in the systematic review, thus not allowing
for meta-analysis).
5. Conclusions
Results of this meta-analysis suggest that chronic
nonparoxysmal patients with OFP present with abnormal EPM
function, represented by increased pain facilitation and a trend
toward impaired pain inhibition. Variety in EPM testing protocols
may have influenced TSP and CPM responses, and could explain
the conflicting results reported by individual studies regarding
EPM efficiency and the considerable heterogeneity found when
aggregating these data into overall effect size estimates. Further
research using EPM is supported by the results of this meta-
analysis to elucidate its mechanistic role in patients with
chronic OFP.
Conflict of interest statement
The authors have no conflict of interest to declare.
Copyright Ó 2018 by the International Association for the Study of Pain. Unauthorized reproduction of this article is prohibited.
www.painjournalonline.com 1453
Acknowledgments
Jim Hodges, PhD, (Division of Biostatistics, School of Public
Health, University of Minnesota) for his assistance in reviewing
drafts of the manuscript.
Appendix A. Supplemental digital content
Supplemental digital content associated with this article can be
found online at http://links.lww.com/PAIN/A578.
Article history:
Received 12 March 2018
Received in revised form 9 April 2018
Accepted 23 April 2018
Available online 26 April 2018
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