Article type : Review

Accepted Article
Evidence for central sensitization in patients with temporomandibular disorders:

a systematic review and meta-analysis of observational studies

Roy La Touche1-4, Alba Paris-Alemany1-4 , Amanda Hidalgo-Pérez1 Ibai López-de-Uralde-Villanueva1-4,

Santiago Angulo-Diaz-Parreño 2,5, Daniel Muñoz-García 1,2.

1
Department of Physiotherapy, Faculty of Health Science, Centro Superior de Estudios Universitarios

La Salle, Universidad Autónoma de Madrid, Aravaca, Madrid.

2
Motion in Brains Research Group, Centro Superior de Estudios Universitarios La Salle, Universidad

Autónoma de Madrid.

3
Institute of Neuroscience and Craniofacial Pain (INDCRAN), Madrid, Spain.

4
Hospital La Paz Institute for Health Research, IdiPAZ. Madrid, Spain.

5
Faculty of Medicine, Universidad San Pablo CEU, Spain.

This article has been accepted for publication and undergone full peer review but has not
been through the copyediting, typesetting, pagination and proofreading process, which may
lead to differences between this version and the Version of Record. Please cite this article as
doi: 10.1111/papr.12604

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 Corresponding Author:

Roy La Touche
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Departamento de Fisioterapia. Centro Superior de Estudios Universitarios La Salle. Universidad

Autónoma de Madrid. Spain.

Motion in Brains Research Group. Instituto de Neurociencias y Ciencias del Movimiento. Centro

Superior de Estudios Universitarios La Salle. Universidad Autónoma de Madrid.

roylatouche@yahoo.es

KEYWORDS: Temporomandibular Joint Dysfunction Syndrome

Myofascial Pain Dysfunction Syndrome

Temporomandibular Joint

Central Nervous System

Running Head: Sensitization in temporomandibular disorders

INTRODUCTION

Temporomandibular disorder (TMD) is a very wide term which includes a variety of clinical issues

related to the masticatory muscles, the temporomandibular joint (TMJ), and their associated

structures 1. For TMD patients the main concern is pain, and it is the most common reason for

medical consultation; but pain makes also a great challenge for clinicians 2. In fact, dysfunction of the

central nervous system when processing nociceptive input has been stated as a factor involved in

the onset and maintenance of pain in patients with chronic TMD 3. In a recent study has been shown

that TMD is associated with emotional distress and multiple comorbidities related to central

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 sensitization (CS) 4. In many cases, CS is the basis of chronic pain, and is responsible for producing

pain hypersensitivity by changing the sensory response elicited by normal inputs 4,5.
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In CS there is an implication of the spino-thalamic tract since a hyperexcitability at the spinal cord

can be found located at the dorsal horn neurons 6. The pathophysiology of CS in TMD is not well

featured yet, but there are some characteristics that have been associated with TMD such as a

decrease in pressure pain threshold (PPT) after receiving a mechanical stimuli in the face or wrist,

and an increase in widespread thermal pain sensitivity and the temporal summation (TS) 7.

Several researchers have evaluated different useful assessments to determine the presence of CS,

and the influence it has on patients with TMD. The sensitivity to noxious or anodyne stimuli can be

assessed with the quantitative sensory testing (QST) which generates and permits the testing of a
8,9
variety of standardize stimulus such as thermal, mechanical, electrical and/or ischemic . In

addition, a large number of researchers have used measurements of central hyperexcitability such as

TS in addition to measurements for evaluating the function of the endogenous pain inhibitory
10–15
system by assessment of conditioned pain modulation (CPM) . TS is obtained when a repetitive

noxius stimuli provokes an increase in pain perception, and it can be explained by a wind-up

phenomenon due to the spinal facilitation of the recurrent stimulation of C-fibers 16. CPM refer to

the reduction in pain sensitivity of a tested stimulus due to the interference of a second stimulus

(conditioning stimulus) applied at the same time but located at a remote body location 9.

To further investigate and increase the knowledge about CS in TMD, the aim of this study was to

carry out a systematic review of pain sensitization in TMD patients in terms of QST and central

hyperexcitability, and a subsequently meta-analysis of the data.

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 METHODS

This research was performed under the guidelines of the “Meta-analysis of Observational Studies in
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Epidemiology” and the “Preferred Reporting Items for Systematic Reviews and Meta-analysis” 17,18.

Inclusion criteria

To include a study in this systematic review it had to meet the following inclusion criteria: 1) Being a

case-control, cohort study, or cross-sectional study regarding the design; 2) Patients consisted of

human adults diagnosed with TMD; 3) Measurements included potentially relevant studies using

QST measures of mechanical hyperalgesia (PPT) and thermal hyperalgesia (hot and cold pain

thresholds) and central hyperexcitability (TS and CPM); 4) Hyperalgesia measured at two points

cathegorized as local (the closest site to the condylar pole of the TMJ) and remote (far form the

primary area of pain or the most distant site from the TMJ) 19; and 5) Studies published in English.

Search Strategy

The scientific articles were searched using MEDLINE (from 1950 to January 2015), EMBASE (from

1988 to January 2016), CINAHL (from 1982 to January 2016), and PsychINFO (from 1806 to January

2016). Also manual reference searches were performed using Google Scholar. The last search was

performed on January 29, 2016.

The strategy used for the search was done following the recommendations of Haynes et al. in order
20,21
to perform a proper selection of the clinical studies which are relevant . This search strategy

combined medical subject headings (MeSH) and other non-MeSH terms, created a string search

adding a Boolean operator (OR and/or AND) to combine the MeSH terms and the subjects areas: 1)

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 temporomandibular disorders; 2) temporomandibular joint dysfunction syndrome; 3) central

nervous system sensitization; 4) hyperalgesia; 5) pain threshold; and 6) pain measurement. The non-
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MeSH terms used included several terms: 1) orofacial pain; 2) temporomandibular joint; 3)

central/peripheral/pain sensitization; 4) hyperalgesia; 5) central hyperexcitability; 6) pain

modulation; 7) hot pain threshold; 8) cold pain threshold; 9) pain pressure threshold; and 10)

temporal summation.

A different strategy search was used depending on the database adapting it as necessary. The search

was conducted by two independent reviewers using the same methods, if any difference emerged

during this phase was resolved by consensus. In addition, reference sections of original studies were

screened manually.

Selection criteria and data extraction

The two independent reviewers performed the first phase of the data analysis assessing the research

relevance of the studies regarding the studies’ questions and objectives. This first analysis was

performed based on information from the title, abstract, and keywords of each study. If there was

no consensus or the abstracts did not contain sufficient information the full text was reviewed.

In the second phase of the analysis, we reviewed the full text and proceeded to check whether the

studies met all of the inclusion criteria. A third reviewer mediated when differences between the

two reviewers appeared, a process of discussion/consensus was performed by the three of them22.

Data described in the results were extracted by means of a structured protocol that ensured the

most relevant information from each study was obtained 23.

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 Methodological quality assessment

The methodological quality of the cohorts and case controls studies selected was assessed using the
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24
Newcastle-Ottawa Quality Assessment Scale (NOS) which has been previously used to analyze
19,25,26
those study designs in other systematic reviews of observational studies . NOS is appropriate

for reviews involving a large number of studies because of its brevity, and it presents a moderate

inter-rater reliability 27. The NOS scores three criteria with a minimum of zero and a maximum of

four stars: grade selection of participants, assessment of exposures and outcomes, and

comparability and control of confounding; based on a total of eight questions. The tallied stars

provide four categories of study quality: 1) poor = 0 to 3 stars; 2) fair = 4 to 5 stars; 3) good = 6 to 7
19,25,26
stars; and 4) excellent = 8 to 9 stars . For the analysis of the methodological quality of the

cross-sectional studies, we used NOS modifications proposed by Fingleton et al. with only three

items: 1) 3/3 was considered a good quality; 2) 2/3 was fair; and 3) 1/3 was poor quality 19.

Two independent reviewers examined the quality of the selected studies using the same methods;

disagreements between reviewers were resolved by consensus including mediation by a third

reviewer. The inter-rater reliability was determined using the Kappa coefficient: 1) > 0.7 means high

level of agreement between assessors; 2) between 0.5 and 0.7 a moderate level of agreement; and

3) < 0.5 a low level of agreement) 28.

Qualitative Analysis

For qualitative analysis of the selected observational studies, an adaptation of the classification

criteria of the results given by Van Tulder et al. for randomized controlled trials was used 29. Results

were categorized into five levels depending on the methodological quality: 1) Strong evidence—

consistent among multiple high quality case-control studies and/or cohort studies and/or cross-

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 sectional studies (at least three of these studies); 2) Moderate evidence—consistent findings from

multiple low quality case-control studies and/or cohort studies and/or cross-sectional studies and/or
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one high quality case-control study and/or cohort study; 3) Limited evidence—one low quality case-

control studies and/or cohort studies and/or at least two cross-sectional studies; 4) Conflicting

evidence—inconsistent findings among multiple studies (case-control and/or cohort and/or cross-

sectional studies); or 5) No evidence—no case-control and/or cohort and/or cross-sectional studies.

Data Synthesis and Analysis

The statistical analysis was performed using meta-analyses with interactive explanations (MIX,

version 1.7) 30 with the data comparing TMD patients to asymptomatic subjects. The same inclusion

criteria were used for the systematic review as well as the meta-analysis but three more criteria

were added: 1) in the results, there was detailed information regarding the comparative statistical

data (mean, standard deviation, and 95% confidence interval) of the QST measures of mechanical

hyperalgesia (PPT) and thermal hyperalgesia (hot and cold pain thresholds) and central

hyperexcitability (TS and CPM); 2) data of the analyzed variables were represented in at least two

studies; and 3) a minimum score in NOS was required: four points for case-control studies and two

points for cross-sectional studies, as inclusion of lower quality studies in a meta-analysis may

overestimate the results 31.

32
Presentation of summary statistics in the form of forest plots was used . Forest plots involve a

weighted compilation of all the standardized mean difference (SMD) and corresponding 95%

confidence interval (CI) reported by each study, and also provide an indication of heterogeneity

between studies. Estimates on the one side of the forest plots indicated increased characteristics of

pain sensitization in TMD patients and were labeled as sensitized, while point estimates on the other

side represented the opposite situation and were labeled as non-sensitized.

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 The statistical significance of the pooled SMD was examined as Hedges’ g, to account for possible
33
overestimation of the true population effect size in small studies . The magnitude of g was
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interpreted according to a four-point scale: 1) < 0.20 = negligible effect; 2) 0.20‒0.49 = small effect;

3) 0.50‒0.79 = moderate effect; and 4) ≥ 0.80 = large effect 34.

The degree of heterogeneity among studies was estimated by the Cochran's Q statistic test (P < 0.1 is

considered significant) and the inconsistency index (I2) 35. I2 > 25 percent is considered to represent a

small, I2 > 50 percent a medium, and I2 > 75 percent a large heterogeneity 36

. I2 index is

complementary to the Q test, although it has a similar problem of power as the Q test with a small

number of studies 36. Therefore, a study was considered heterogeneous when fulfilling one or both

of these conditions:1) Q-test was significant (P < 0.1), 2) the result of I2 was > 75%; and a random-

effects model as described by DerSimonian and Laird was conducted in the meta-analysis of the

heterogeneous studies to obtain a pooled estimate of effect 37.

To detect the existence of publication biases and test the influence of each individual study, a visual

evaluation of funnel plot and exclusion sensitivity plot, searching for any asymmetry, was

performed. Also, the Egger's regression test was used to test for bias 38,39.

RESULTS

The study search strategy is presented in the form of a flow chart (Figure 1). Finally, 22 articles
3,40–60
(eleven case-control studies and eleven cross-sectional studies) met the inclusion criteria , of

which eight were included in the meta-analysis (five cross-sectional and three case-control studies).

Descriptive characteristics of the studies included in this study are present in Table 1.

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 Characteristics of the Study Population

All patients in the studies had pain in TMJ area for at least three months. As for the pain
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3,42,43,46–
characteristics in the experimental group, eleven studies included data about myofascial pain
49,51,58–60 52,53,56,57
four of the studies included mixed pain (myogenous and arthrogenous) , and one

study referred only to arthrogenous pain 40. In addition, four studies referred to non-specific orofacial
41,44,50,54 45,55
pain , and two studies did not describe the characteristics of pain . Eight-hundred twenty-

seven patients were included. The percentage of women participating in the studies ranged from
51 3,41,44–47,49,54,59,60
62.8% to 100% , except in five studies in which this information was not specified
43,50,52,55,58
. The range of ages included in the inclusion criteria of the analyzed studies was from 18 to

65 years 51,52.

Methodological quality

The articles’ quality was acceptable. Scoring was performed by two researchers separately. The inter-

rater reliability of the methodological quality assessment was moderate (κ = 0.67).

Some lack of consistency was resolved by re-reviewing a few articles in-depth with a third evaluator

until a consensus for all items was reached. Detailed information on methodological quality scores is

shown in Tables 2 and 3.

Five of the case-control studies were scored as good quality 3,45,52,55,60 while six studies were scored as

fairly quality 41,43,44,53,57,59, and one other received a poor quality score 40.

All the cross-sectional studies 42,46,47,49–51,54,56,58 were scored as fair quality except for one 48, which was

considered poor quality.

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 All studies exceeded the 40% threshold for inclusion in this review. The methodological evaluation

was penalized in most cases because the control group was not representative of the community cases.
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The exposure assessment was not blinded, which may be an important factor for the outcomes of the

pain experimental protocols developed in some studies. Moreover, neither of the case control studies

exhibited non-response rates of the participants at the end.

Evidence for central sensitization

1. Pressure pain thresholds

Twelve studies analyzed the presence of hyperalgesia in patients with TMD using measures of PPT 40–
44,47,48,52,53,55,57,58
. All of these studies compared PPTs in TMD participants with asymptomatic controls
41,44,47,52,53,58
using handheld pressure algometry, and six of them were included in the meta-analysis .

All of the studies herein included had a remote pain location associated with the presence of central

sensitization. However, the distance to the measuring point was different for most of the studies.

Three studies used the thenar muscle, two chose the lateral epicondyle, and two others choose the
43,44,47,48,52,55,57
tibialis anterior . Sternum, Achilles tendon, index finger and forearm were the other

locations chosen as distal points 40–42,47,53,58.

Ten of the twelve studies concluded that PPT was significantly lower for TMD subjects when

compared with asymptomatic subjects 40,42–44,47,48,52,55,57,58.

The study of Mohn et al. showed that there were no differences between the TMD and control groups

in PPT measure, although the effect sizes for PPT were very low, which indicates that even with

larger samples these group differences would still be rather small 41. Finally, in the study of Oono et

al., the analysis of PPT values revealed no differences in any of the subject groups, but significant

differences among the three assessment sites, with significantly higher PPT values at the forearm

compared with the TMJ and masseter 53.

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 The meta-analysis of local PPTs showed strong evidence in favor of greater trigeminal pain sensitivity
44,47,52,53,58
pressure in patients with TMD (five studies : n = 1985; SMD = -1.55, 95% CI -2.23‒-0.77;
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Figure 2). There was evidence of a large statistical heterogeneity (Q value= 39.7; I2 = 89.9%; P =

0.051). Similarly results of meta-analysis of Remote PPTs (5 studies 44,47,52,53,58: n = 1985; SMD = -1.92,

95% CI -2.95‒-0.89; Figure 2) in favour of greater remote pressure pain sensitivity in patients with

TMD. Large heterogeneity was observed in this meta-analysis (Q value= 63.2; I2 = 93.6%; P = 0.061).

With the exception of one study previously judged as having a high risk of bias and implausibly large

effects 47, the shape of the funnel plot seemed to be asymmetrical in the dominant model as judged

by visual examination for local and remote areas (Figure 3). The influence of each individual study

was assessed with a sensitivity exclusion analysis (Figure 4). Statistically strong results were obtained

since the analysis suggested that no individual studies significantly affected the pooled SMD. The

similarity found among the pooled estimates suggests that there is not a single study influencing the

results of the meta-analysis in a disproportionately manner. Accordingly, the Egger's test of

asymmetry was applied and the results suggested no significant evidence for publication bias for

analysis the local (Intercept = −3.209; t = -1.96; P = 0.14) and remote PPTs (Intercept = −4.28; t = -

2.48; P = 0.089).

2. Cold pain thresholds

Two studies used CPT’s as hyperalgesia measure; both of these studies showed that there was a
46,56
significant cold hyperalgesia (decreased CPT) in TMD patients . In fact, Fernández de las Peñas

et al. concluded that the magnitude of cold hyperalgesia in the trigeminal region was associated with

the duration and intensity of TMD pain symptoms 46.

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 According to the results of the meta-analysis, a cold hyperalgesia in trigeminal local (two studies: n =

91; SMD = 2.08, 95% CI -0.82‒4.98; Figure 5) and remote areas (two studies: n = 91; SMD = 1.9, 95%
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46,56
CI 1.46‒5.25; Figure 5) for the group of patients with TMD were not found . Heterogeneity was

large (local; Q value= 23.2; I2 = 95.7%; P = 0.14/ Remote; Q value= 31.04; I2 = 96.7%; P = 0.25).

3. Heat pain thresholds

Three studies found that there was no difference in sensitivity to HPT between TMD subjects and
43,45,49
controls . Five studies showed that TMD subjects had more pain sensitivity in terms of HPT

than pain-free subjects 42,46,50,52,56.

In summary, the qualitative analysis revealed mixed results for heat hyperalgesia measured by HPT’s.

However, the meta-analysis comparing local and remote HPTs between patients with TMD and

asymptomatic subjects indicated that there were no significant differences in heat pain sensitivity
46,49,56
between groups (local; three studies : n = 127; SMD = -1.56, 95% CI -3.22‒0.1/ remote; 4
46,49,52,56
studies: n = 1945; SMD = -0.97, 95% CI -2.07‒0.14; Figure 6) . Large heterogeneity was

present in this meta-analysis (local; Q value= 29.27; I2 = 93.1%; P = 0.044/ remote; Q value= 49.4; I2 =

93.9%; P = 0.107).

Similar results for the analysis of publication bias of PPTs with HPTs using the visual analysis of the

funnel plot was observed. Asymmetry due to a study that was previously judged as having a high risk

of bias and implausibly large effects was found (Figure 7). A sensitivity exclusion analysis was

performed to assess the influence of each individual study (Figure 8). The results suggested that no

individual studies significantly affected the pooled SMD indicating a statistically robust result.

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 However, the Egger's test of asymmetry was not significant for publication bias for analysis of the

local (Intercept = −14.90; t = -2.15; P = 0.27) and remote PPTs (Intercept = −2.59; t = -0.77; P = 0.51).
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4. Temporal summation

3,44,52,57,60
Five studies demonstrated increased facilitation of mechanical TS in TMD patients . Sarlani

et al. demonstrated that after repetitive noxious stimulation appears a more pronounced temporal

summation of pain and greater after-sensations, in an area remote to the face and head in a group of

TMD patients 3. However, Sato et al. showed that TS was not observed in any of the groups, but after-

sensations were consistently reported 54. Finally, significant differences were found in terms of gender

by Sarlani et al.; they found that neither asymptomatic men nor TMD male patients exhibited
51
statistically significant temporal summation of mechanically evoked pain . Notably, the lack of

temporal summation was very consistent across the male TMD patient group.

In terms of the TS of heat pain, the three articles referring to this measurement concluded that the heat

pain TS measurements did not show statistically significant differences between patients with TMD
49,50,52
and asymptomatic subjects . In summary, no strong evidence for spinal hyperexcitability was

found in relation to the mechanical TS.

5. Conditioned pain modulation

Two studies demonstrated a dysfunctional CPM response in patients with TMD with an apparently
44,59
non-effective pain inhibitory system . However, Kothari et al. and Garrett et al. found that there
57,60
were no significant differences in CPM between the TMD group and asymptomatic subjects .

Finally, Oono et al. showed that in the TMD patients, no CPM effects assessed at the trigeminal

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 53
region could be found, although CPM assessed at the spinal region was found . Thus, conflicting

evidence for dysfunctional endogenous nociceptive inhibition was presented.

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DISCUSSION

A systematic review and meta-analysis was conducted regarding the processes of pain sensitization

and central hyperexcitability in TMD patients. Significant results based on the meta-analysis revealed

large SMDs in mechanical pressure pain sensitivity in the trigeminal region and remote regions in

patients with TMD when compared with asymptomatic subjects, which is suggestive of peripheral

and central nervous system sensitization in this patients. In addition, the qualitative analysis showed

strong evidence that spinal and central hyperexcitability was demonstrated in TMD patients in seven

studies of this review as demonstrated by an increase in TS. The findings of mechanical TS and

widespread mechanical hyperalgesia associated with TMD patients, suggest the existence of a process

of CS. In relation to this, Latremoliere and Woolf stated that "CS is responsible for many of the

temporal, spatial, and threshold changes in pain sensibility in acute and chronic clinical pain settings

and exemplifies the fundamental contribution of the central nervous system to the generation of

pain hypersensitivity” 5. The findings reported in this systematic review and meta-analysis are in line

with previous research about the sensitization characteristics reported in other chronic pain conditions
19,26,61–63
.

TMD patients usually present with widespread pain, which suggests a generalized hyperexcitability 64.
65
Previous research has related muscular pain mainly with central hyperexcitability . In most of the

studies that we analyzed, the patients with TMD suffered muscular or a mixed articular and muscular

pain condition. Functional and structural changes have also been found in TMD patients with chronic

orofacial pain mainly due to muscle tension and biomechanical alterations during a large period of
66,67
time can accelerates TMJ degeneration . Moreover, alterations in this region are also associated

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 with cervical pain. Previous studies describe that the severity of TMD patients increased with neck
68,69
pain aggravation . Nevertheless, the absence of positive clinical and image tests in chronic pain
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patients is also frequently absent, which facilitates the search for medical care and raises patients

concerns about their symptoms 70.

In the qualitative analyses of the thermal pain thresholds, the results are conflicting. Our data did not

show differences in the HPT and CPT between TMD patients and asymptomatic subjects. Previous

studies support that through physical thresholds (such as thermal or pressure) central sensitization can

be determined, but Hübscher et al. concluded that either pain thresholds were not strong indicators of

central sensitization or sensitization was not an important factor in patients with pain and disability71.

The variability in the results of the thermal pain threshold could be caused by the heterogeneous

measurement protocols used in some analyzed studies allowing subjects to hold the thermode

assembly themselves during the termal test which may have introduced variation in contact among

subjects 49. It is interesting to have into account that the order of the quantitative sensory testing itself

can lead to mechanical hyperalgesia after the thermal testing and an habituation effect can occur
72–74
specially if the inter-trial intervals are lower than 60 seconds . Also in many of the analyzed

studies, psychosocial factors were not taken into account when interpreting the results, and it has been
75–77
observed that these factors may be associated with hyperalgesia . Specially, anxiety was studied
78
before as a contributor in higher sensitization process and hiperalgesia in chronic patients which

could enhanced memory of pain and anticipate pain sensations despite of the stimulus 79. Regarding

depressive disorders they could directly affect QST including HPT 80,81.

Along this line, negative beliefs of the patient about the understanding their chronic condition could

also complicate the evolution of the disease; this could lead to the fear avoidance model proposed by

Vlaeyen and Linton with patients tending to reduce physical activity and further increasing their

disability 82,83.

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 Finally, evidence also suggests that the thermal pain threshold data were influenced by the level of

intensity of previous pain especially in patients with moderate and severe symptoms who showed
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14,84,85
larger differences compared with asymptomatic patients . There are some lacks in the analyzed

studies since they did not perform a sub-classification of patients regarding the severity and chronicity

of pain, which might have brought interesting results. The studies of Fernández-de-las-Peñas et al. 47
56
and Park et al. analyzed patients with higher pain chronicity which could lead to lower thermal

thresholds 86. Moreover, Park et al.56 and Greenspan et al.52 included males and females which could

lead to variations in the results because of hormones differences that were neither controlled among
87
females performing the measurements at the same menstrual cycle . QST are considered an
8
assessment toll to identify CS and have been used by many researchers investigating various
8,88–90
musculoskeletal conditions , more over they have demonstraded the ability to discriminate

between central and peripheral sensitization88.

Future studies should control for this issues to detect thermal pain threshold, which could be a useful

clinical tool for identifying patients at a risk for poorer results to varied treatment approaches and

those TMD patients with pain modulation changes in neck regions 91,92.

The qualitative analysis from this systematic review showed conflicting evidence that endogenous

pain inhibitory mechanisms such as CPM are altered in patients with TMD. There are very few

studies on the subject of CPM regarding TMD, and the results of these are mixed. Further studies are

needed to clarify the topic of endogenous analgesic function in patients with TMD, and they should

include assessment of patients’ expectations and other psychological factors that have

demonstrated an influence over the pain processing and modulation mechanisms 93,94.

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 Clinical and scientific implications

The obtained data herein could be helpful for clinicians to detect signs of central sensitization in
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patients with TMD and establish a classification based on this item and direct treatment to improve

management of the pathology. Establishment of a clinical protocol, including the assessments of PPT

in trigeminal and extra-trigeminal areas, could provide information about the presence of local or

generalized hyperalgesia. From the technical point of view, scientific evidence confirms that the

algometer is an easy to use device with proven reliability for measuring PPTs in several

musculoskeletal disorders.

Identifying the processes of CNS sensitization in TMD patients, should lead to new therapeutic

approaches based on the bio-behavioral paradigm focused on different related factors with the

central sensitization, and establishment of treatments that integrate sensory, cognitive, emotional

and motor dimensions of the disorder.

Recognizing the deficits that the studies included in this review present should serve to generate

new research that integrates the measurements of QST with measurements of disability, pain

intensity, and psychosocial factors that may be involved in the processing and transmission of pain

at peripheral and central levels.

Limitations

There are some limitations in this study. First, the pathology of the subjects, although all of them

presented craniofacial pain, varied depending on the origin: 1) muscular; 2) arthorgenous; 3) a

combination of them; or 4) non-specific. Second, the methodological quality of the included studies

is stated as good or fair for most of them as international criteria recommends, except for one of

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 them, which was classified as poor and could influence the results of this systematic review 95. Third,

the research was done in English and Spanish, which limited the obtained results and sets aside
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other possible interesting investigations published in other languages. Finally, we did not include

data regarding clinical pain, and our data was only focused on sensivity responses from lab tests.

Moreover, when combining studies in the meta-analysis to examine the central sesitization at distal

regions there was some heterogeneity in this locations between studies.

CONCLUSIONS

This meta-analyses supports the existence of differences in pain sensitivity in trigeminal and remote

regions, as assessed with mechanical thresholds, in patients presenting with TMD when compared

with asymptomatic subjects. This finding is suggestive of peripheral and central nervous system

sensitization in these patients. Spinal and central hyperexcitability can also be found in TMD

patients, as exhibited by increased mechanical TS.

CONFLICT OF INTEREST STATEMENT

There are no conflicts of interest.

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Accepted Article
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ccepted Articl
Table 1. Characteristics of included studies

Article Design
Sample
characteristic
s of TMD
group
Sample
characteristics
of control
group
Mean duration
of symptoms in
TMD group
Inclusion criteria in
TMD group

Report of spontaneous
Hyperalgesia
measures
Measures of
CH
General conclusion
regarding central
sensitization

pain or pain on
movements in the TMJ
N=20 N=43 (during lateral Persons with TMJ
excursions, maximum arthralgia had markedly
Ayesh et al PPT (TMJ, No measure
Case-control 3 (M); 17 (F) 24 (M); 19 (F) Not stated unassisted opening, or lower pressure thresholds
2007 index finger). of CH used.
assisted opening), and on the TMJ and finger than
Age: 20-39. Age: 19-32 pain on palpation of the did healthy individuals.
lateral pole or posterior
attachment of the TMJ
on the same side.
TMD and pain-free subjects
N=22 (F)
did not differ with respect
N=20 (F) to onset or tolerance of
Age:
thermal pain. Novel
Age: 27.09±1.04
Bragdon et al Case-control No measure demand characteristics
Not stated Undescribed HPT (arm).
2002 of CH used. sensitized the pain-free
N=20 (F)
26.00±1.35 women to the pain stimuli,
diminishing the difference
Age:
between their responses and
25.05±1.15
those of the TMD patients.
The fndings revealed
bilateral thermal
hyperalgesia in women
Patients diagnosed with
with myofascial TMD as
exclusively myofascial
compared to healthy
TMD, spontaneous pain
controls. These results may
involving the masseter
Fernández de Cross- N=20 (F) N=20 (F) HPT (frontalis, reflect a dysfunction of
muscle with duration of No measure
las Peñas et al sectional 23,1 months masseter, wrist). thermal channels in
at least 6 months, and of CH used.
2009 study Age: 24±3 Age: 24±4 CPT (idem). myofascial TMD patients
an intensity of at least 3
as result of some
on an 11-point
combination of peripheral
numerical pain rating
sensitization, facilitation of
scale.
central nociceptive
processing and/or decreased
descending inhibition.

This article is protected by copyright. All rights reserved.

ccepted Articl Article Design
Sample
characteristic
s of TMD
group
Sample
characteristics
of control
group
Mean duration
of symptoms in
TMD group
Inclusion criteria in
TMD group

Patients diagnosed with

TMD, spontaneous pain
Hyperalgesia
measures

PPT (supra-
orbital, infra-
orbital , mental
Measures of
CH
General conclusion
regarding central
sensitization

The study reveals a bilateral

and widespread decrease in
PPT in nerve, joint, and
nerves, median,
involving the masseter muscle tissues in
N=16 (F) N= 20 (F) radial and ulnar
Fernández de Cross- 22.8 months muscle with a duration myofascial TMD women
nerve trunks, No measure
las Peñas et al sectional (95% CI 14.9- of at least 6 months and when compared to healthy
Age: 20-28 Age: 20-29 the C5-C6 of CH used.
2010 study 30.8 months) an intensity of at least 3 controls, suggesting that
years. years. zygapophyseal
on an 11-point central sensitization is
joint, the lateral
numerical pain rating involved in women
pole of the
scale. presenting with myofascial
TMJ, and the
TMD.
tibialis anterior).
Pain ratings increased
significantly with stimulus
N= 30 (F) Primary diagnosis of repetition and CPM
N= 30 (F) No measure of
Garrett et al masticatory myofascial TS significantly reduced TS of
Case-control Not stated hyperalgesia
2013 Mean age: pain, according to the CPM pain. Both groups showed
Mean age: 36.7 used
36.3 RDC for TMD very similar degrees of
CPM, with no significant
group differences.
Chronic TMD cases are
Pain reported with
more sensitive to many
frequency in the cheeks,
experimental noxious
jaw muscles, temples or
stimuli at extra-cranial
jaw joints during the
PPT (temporalis body sites, and provides for
preceding six months,
muscle, the first time the ability to
pain reported in the
N= 1633 masseter directly compare the case-
N= 185 examiner-defined
(M and F) muscle, TMJ, Heat pain TS control effect sizes of a
Greenspan et al orofacial region for at
Case-control Not stated trapezius Mechanical wide range of pain
2011 Age: 18-44 least 5 days out of the
Age: 18-44 muscle, lateral pain TS. sensitivity measures.
years. prior 30 days; and pain
years. epicondyle).
reported in at least three
HPT (ventral
masticatory muscles or
forearm)
at least one TMJ in
response to palpation of
the orofacial muscles or
maneuver of the jaw.

This article is protected by copyright. All rights reserved.

ccepted Articl Article Design
Sample
characteristic
s of TMD
group
Sample
characteristics
of control
group
Mean duration
of symptoms in
TMD group
Inclusion criteria in
TMD group
Hyperalgesia
measures
Measures of
CH
General conclusion
regarding central
sensitization
The ability to activate the
mechanism of endogenous
modulation is impaired in
PPT(the body of women with myofascial
the masseter pain of the masticatory
muscle at pain muscles. In fact, the TMD
N=20 (F) N=20 (F) Patients diagnosed
Pain present for side or at the group showed lower
Hilgenberg et al according to the TS
Case-control at least 6 most painful pressure pain thresholds
2015 Age: Age: American Academy of CPM
months side, the than control group. These
45.5±7.54 37.85±10.25 Oro-facial Pain criteria.
cervical zone results reinforce evidence
and the thenar of central sensitisation and
eminence). impaired endogenous
modulation system in
individuals with this
syndrome.
Compared to controls,
TMD patients reported
TMD patients had to
N= 14 (F) increased sensivity to heat
N= 28 (F) meet the RDC for TMD
No measure of pain and failed to
for an Axis I Group I
King et al 2009 Case-control Age: Not stated hyperalgesia CPM demonstrate pain inhibition
Age: 28.6±10.8 diagnosis (myofascial
31.0±10.2 used due to DNIC. Controls
TMD) at the time of
showed a significant
evaluation
reduction in pain during the
DNIC session.
Patients with TMD pain
belonging to group IIIa
or group IIIb from Somatosensory
N=34
N=34 RDC/TMD. Additional abnormalities were
diagnoses of myofascial commonly detected in
Kothari et al 27 (F); 7 (M) Longer than 3 PPT (TMJ and TS
Case-control 25 (F); 9 (M) pain (group I) and disk TMD pain patients and
2015 months thenar muscle). CPM
displacements (group CPM effects were similar in
Age: 33.0 ±
Age: 30.1±1.9 II) to group IIIa or IIIb TMD pain patients and
1.8
from RDC/TMD healthy controls.
protocol were also
accepted.

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ccepted Articl Article Design
Sample
characteristic
s of TMD
group
Sample
characteristics
of control
group
Mean duration
of symptoms in
TMD group
Inclusion criteria in
TMD group

Aged between 25 and

Hyperalgesia
measures
Measures of
CH
General conclusion
regarding central
sensitization
The findings of the present
study show topographic
variations in the pain
responses to different
55 years diagnosed with
stimulus modalities.
myofascial pain of the
Cross- N=20 (F) N=20 (F) PPT (masseter Different pain responses
Michelotti et al masticatory muscles No measure
sectional Not stated and thenar were also found between
2008 (Axis I – Group I) of CH used.
study Age: 45.5±7.8 Age: 37.8±11 muscle). patients with myofascial
according to the
pain and control subjects
Research Diagnostic
and were interpreted to
Criteria for TMD.
support theories of centrally
mediated pain for temporo-
mandibular disorders.
Orofacial pain for at
N=25 (F) least 3 months and a PPT (right No statistically
N=25 (F)
Mohn et al Case-control pain level high enough masseter No measure significant group
8.35±7.3 years
2008 Age: to seek treatment. muscle, of CH used. differences were found in
Age: 33.9±11.1
35.2±11.9 sternum). pressure pain sensitivity.
Adults over the age of
18, pain-free subjects
except for TMD, and The results indicated that
TMD pain patients from PPT can be modulated by
N= 16
N=16 RDC/TMD (TMJ CPM effects. The findings
osteoarthritis (IIIb) PPT (TMJ, are consistent with the
14 (F); 2 (M)
Oono et al 2015 Case-control 14 (F); 2 (M) Not stated from RDC/TMD, i.e., masseter, CPM present study that CPM can
TMJ arthralgia (type forearm). be demonstrated with
Age: 43.0 ±
Age: 38.9 ± 3.4 IIIa, pain in the TMJ) painful test stimuli (PPT)
4.0
plus either coarse but not with non-painful
crepitus in the joint or stimuli.
degenerative changes in
the joint).

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ccepted Articl Article Design
Sample
characteristic
s of TMD
group
Sample
characteristics
of control
group
Mean duration
of symptoms in
TMD group
Inclusion criteria in
TMD group

Patients diagnosed with

Hyperalgesia
measures

HPT (anterior
temporal,
Measures of
CH
General conclusion
regarding central
sensitization
The results suggest that
peripheral and/or central
sensitization are present in
N=39 TMD according to the masseter, TMJ
N= 36 chronic TMD, and this
Research Diagnostic and anterior
Cross- phenomenon appears to
7 (M); 32 (F) Criteria for TMD, and tibialis). No measure
Park et al 2010 sectional 7 (M); 29 (F) Not stated take place regardless of the
patients who reported CPT (anterior of CH used.
study patient’s psychological
Age: high Graded Chronic temporal,
Age: 29.0±7.0 profiles. These results may
30.8±11.7 Pain (GCP) scale masseter, TMJ
explain the underlying
scores. and anterior
mechanism that aggravates
tibialis)
TMD pain.
PPT (masseter Sensitive TMD patients
N=23 Chronic uni- or bilateral muscle, showed a generalized
N=18
myofascial pain in the trapezius pressure hyperalgesia over
Cross- Pain present for
20 (F); 3 (M) face and exclusion of muscle, thenar No measure all test areas, cold pain
Pfau et al 2009 sectional 15 (F); 3 (M) at least 6
other face-related pain eminence) of CH used. hyperalgesia over trapezius
study months.
Age: origins like neuropathic HPT (cheek, and cheek and heat pain
Age: 47.6±14.5
46.8±13.1 pain. trapezius, hand). hyperalgesia over all test
CPT (idem). areas.
The results are consistent
Women, between ages
with the presence of
N=19 (F) 18–65, diagnosed with
Cross- N=17 (F) HPT (thenar enhanced central sensitivity
Raphael et al TMD (muscle origin) TS of heat
sectional 12 months eminence and in TMD and suggest that
2009 Age: and fulfillment criteria pain.
study Age: 37.5±13.8 maxillary skin) this sensitivity may be
36.2±13.1 for a myofascial
largely confined to the
subtype of TMD.
region of clinical pain.
Between the ages of 18 Significant between-group
and 45 years, no differences in HPT were
ongoing chronic pain not observed. TMJD
problems other than patients demonstrated
TMJD, no systemic significantly greater
N= 49 N=70 medical condition, not hyperalgesia than healthy
Cross-
Ribeiro et al 32(F); 17 (M) 37 (F); 33(M) pregnant, use of HPT (ventral TS of heat controls, but there were no
sectional 42±31 months
2012 analgesics, forearm). pain. differences for TS.
study
Age: 24.6±5.5 Age: 24.6±5.5 antidepressants or other
centrally acting agents,
and no mental health
disorders requiring
hospitalization in the
past year.

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ccepted Articl Article Design
Sample
characteristic
s of TMD
group
Sample
characteristics
of control
group
Mean duration
of symptoms in
TMD group
Inclusion criteria in
TMD group

Patients diagnosed with

Hyperalgesia
measures
Measures of
CH
General conclusion
regarding central
sensitization
A generalized
hyperexcitability of central
nociceptive processing in
TMD according to the this TMD patient group is
Research Diagnostic indicated by their more
Criteria for TMD, pain pronounced temporal
N=25 (F) N=25 (F)
originating from the No measure of summation of pain and
Sarlani et al
Case-control Not stated jaw, temples, face, or hyperalgesia TS greater aftersensations
2004 Age: 38.9 (21- Age: 38.8 (23-
around or inside the ear, used. following repetitive
57) 54)
as well as pain upon noxious digital stimulation
palpation of 3 or more versus controls. Such
of 20 facial muscle hyperexcitability may
sides. contribute to the
phatophisiology of TMD
pain.
Primary diagnosis of
masticatory myofascial
pain according to the
N= 27 (F) RDC/TMD .
Masticatory myofascial
Mean age: N=20 (M) pain involves pain Central nociceptive
Cross- 36.1 years originating from the No measure of processing upregulation is
Sarlani et al TS
sectional Age: 37.8 years Not stated jaw, temples, face, hyperalgesia likely to contribute to TMD
2007
study N= 16 (M). (age range, 19 periauricular area, or used. pain for women but is not a
to 67 years) inside the ear during factor for men with TMD.
Mean age: rest or during function,
35.9 years as well as pain upon
palpation of at least 3 of
20 specific masticatory
muscle sites.
The duration of
aftersensations in the
Complaints of orofacial tension- type
N= 13 (F) N= 20 (F)
Cross- pain in the masseter No measure of headache/TMD group was
Sato et al 2012 sectional Not stated and/or temporalis areas hyperalgesia TS significantly longer than in
Age: 28.8 ± Age: 22.95 ±
study for a duration of more used. the control group in both
9.8 4.6
than 3 months. the trigeminal and
extratrigeminal nerve
territories.

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ccepted Articl Article Design
Sample
characteristics
of TMD group

Persistent TMD
group: N=72.
69(F): 60(M)
Sample
characteristics
of control
group
Mean duration
of symptoms in
TMD group
Inclusion criteria in
TMD group
Hyperalgesia
measures

PPT (temporalis
muscles,
Measures of
CH
General conclusion
regarding central
sensitization
Pressure pain thresholds
reduced when TMD
developed then rebounded
Age: 29 ± 1.0 when TMD resolved.
N= 126 masseter
However, pre-morbid
Case- 63 (F); 51 (M) muscles, TMJ, No measure
Slade et al 2014 Transient TMD Not stated Undescribed pressure pain thresholds
control trapezius of CH used.
cases: N=75. poorly predicted TMD
Age: 29 ± 0.7 muscles, and the
57(F);36(M) incidence, countering the
lateral
Age: 31 ± 1.1 hypothesis that they signify
epicondyles).
mechanisms causing first-
onset TMD.
N=22 A primary diagnosis of
16 (F); 6 (M) myofascial pain
according to the PPTs were lower in the
Age: 38.8 ± 3.8 research diagnostic myofascial TMD patients
N=21
criteria for TMD, pain compared to the control
15(F); 6(M)
Cross- Pain present for involving the masseter PPT (masseter, group, both in the masseter
Svensson et al No measure
sectional at least 6 muscle, a duration of anterior tibialis). and in the anterior tibialis,
2001 Age: 38.8 ± 3.8 of CH used.
study months. pain of at least 6 HPT (idem). whereas there were no
months, and an intensity significant differences in
of pain corresponding to HPT.
a weekly average of at
least 3 cm on a 10 cm
visual analogue scale.

RDC: Research Diagnostic Criteria; M: males; F: females; TMJ:Temporo-mandibular joint; PPT: pressure pain threshold; TMD: temporomandibular disorder; HPT: heat pain threshold; CH:

Central Hiperexcitability; CPT: cold pain threshold; TS: temporal summation; CPM: conditioned pain modulation; DNIC: Diffuse Noxious Inhibitory Control.

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ccepted Articl
Table 2. Quality appraisal case-control studies

Case- S1: S2: S3: S4: Ca: Cb: E1: E2: Same E3: Total %
control Adequate Represent Selection Definition Control Controlled Ascertainment method for Non-
studies case ativeness of of led for for of exposure cases & response
definition of cases controls controls age/gen additional controls rate
der factor
Ayesh 2007 ★ ★ ★ ★ 4/9 44
Bragdon 2002 ★ ★ ★ ★ ★ ★ ★ 7/9 78
Futarmal-
Kothari 2015 ★ ★ ★ ★ ★ 5/9 56
Garrett 2013 ★ ★ ★ ★ ★ ★ 6/9 67
Greenspan
2011 ★ ★ ★ ★ ★ ★ ★ 7/9 78
HilGenBerg-
Sydney 2016 ★ ★ ★ ★ ★ ★ 6/9 67
King 2009 ★ ★ ★ ★ ★ 5/9 56
Mohn 2009 ★ ★ ★ ★ ★ ★ 6/9 67
Sarlani 2004 ★ ★ ★ ★ ★ ★ ★ 7/9 78
Slade ★ ★ ★ ★ ★ ★ ★ ★ 8/9 89
Oono 2014 ★ ★ ★ ★ ★ ★ 6/9 67
Svensson 2001 ★ ★ ★ ★ ★ ★ 6/9 67

S = selection; C = comparability; E =exposure

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ccepted Articl
Table 3. Quality appraisal cross-sectional studies

Cross S1: S2: Selection S3: S4: Ca: Cb: Study O1: Ax of O2: Long O3: Total %
sectional Representativeness of non- Ascertainment Outcome Study controls outcome enough Adequate
studies of exposed cohort exposed of exposure * of interest controls for * follow-up follow-
* cohort not for additional up
present at age/gend factor
start er
Alves Da
Costa 2015 - ★ - - - ★ - - 2/3 67
De las Peñas
2009 - ★ - - - ★ - - 2/3 67
De las Peñas
2010 - ★ - - - ★ - - 2/3 67
Michelotti
2008 - ★ - - - - - 1/3 33
Park 2010 - ★ - - - ★ - - 2/3 67
Pfau 2009 - ★ - - - ★ - - 2/3 67
Raphael
2009 - ★ - - - ★ - - 2/3 67
Ribeiro
Dasilva 2012 - ★ - - - ★ - - 2/3 67
Sarlani 2007 - ★ - - - ★ - - 2/3 67
Sato 2012 - ★ - - - ★ - - 2/3 67

S = selection; C = comparability; O = outcome

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 LEGENDS
Accepted Article
Table 1. Characteristics of included studies. RDC: Research Diagnostic Criteria; M: males; F:

females; TMJ:Temporo-mandibular joint; PPT: pressure pain threshold; TMD: temporomandibular

disorder; HPT: heat pain threshold; CH: Central Hiperexcitability; CPT: cold pain threshold; TS:

temporal summation; CPM: conditioned pain modulation; DNIC: Diffuse Noxious Inhibitory Control.

Table 2. Quality appraisal case-control studies. S = selection; C = comparability; E =exposure

Table 3. Quality appraisal cross-sectional studies. S = selection; C = comparability; O = outcome

Figure 1. PRISMA flow diagram

Figure 2. Syntesis Forest plot for pressure pain thresholds (PPT). This forest plot summarizes the

results of the 5 included studies (simple size, standarized mean differences and weight). The small

boxes with the squares represent the point estimate of the effect size and sample size. The lines on

either side of the box represent a 95% confidence interval.

Figure 3. Publication bias heterogeneity funnel plot for pressure pain thresholds (PPT) of local (a)

and remote (b) points. A funnel plot was used to assess risk of publication bias. A symmetrical funnel

plot is an indicator for lack of bias in a meta-analysis. A funnel plot analysis included a total of 5

studies. The diagonal lines represent the limits of 95% confidence. The funnel plot for this final

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 analysis was not fully symmetrical, but publication bias cannot be concluded based on the results of

Egger's regression test and the analysis of exclusion sensitivity plot.

Accepted Article
Figure 4. Exclusion sensitivity plot for pressure pain thresholds (PPT). The omitting Fernandez-de-las-

Peñas et al (2009), study did not produce a significant change in the estimate of effect size, as it

contributed relatively little to the final weighted estimate. Random-effects model was used.

Figure 5. Syntesis Forest plot for cold pain thresholds (CPT). This forest plot summarizes the results

of two included studies (simple size, standarized mean differences and weight). The small boxes with

the squares represent the point estimate of the effect size and sample size. The lines on either side

of the box represent a 95% confidence interval.

Figure 6. Syntesis Forest plot for heat pain thresholds (HPT). The results included a total 3 studies for

local points and 4 studies for remote points. This forest plot summarizes the results of all included

studies (simple size, standarized mean differences and weight). The small boxes with the squares

represent the point estimate of the effect size and sample size. The lines on either side of the box

represent a 95% confidence interval.

Figure 7. Publication bias heterogeneity funnel plot for heat pain thresholds (HPT) of local (a) and

remote (b) points. A funnel plot was used to assess risk of publication bias. A symmetrical funnel plot

is an indicator for lack of bias in a meta-analysis. A funnel plot analysis included a total of 3 studies

for local points and 4 studies for remote points. The diagonal lines represent the limits of 95%

confidence. The funnel plot for this final analysis was not fully symmetrical, but publication bias

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 cannot be concluded based on the results of Egger's regression test and the analysis of exclusion

sensitivity plot.
Accepted Article
Figure 8. Exclusion sensitivity plot for heat pain thresholds (HPT). The omitting Fernandez-de-las-

Peñas et al (2010), study did not produce a significant change in the estimate of effect size, as it

contributed relatively little to the final weighted estimate. Random-effects model was used.

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 Figure 1. PRISMA flow diagram.
Accepted Article
Records identified through Additional records identified
database searching through other sources
Identification

(n = 649 ) (n = 15 )

Records after duplicates removed Records excluded

(n = 48 )
(n = 115 )
Reason for exclusion

- Not observational studies: n=12

Screening

Titles, Abstracts screened - Not diagnostic TMD: n=13

(n = 77) -Study of pain processing not
quantitative sensory testing: n=15

- They did not perform compared to

Full-text articles assessed asymptomatic subjects:
Full-text articles n=8
excluded,
for eligibility with reasons
(n = 29) (n = 7)
Eligibility

-Study of pain processing

not quantitative sensory
Studies included in
testing: n=4
qualitative synthesis
(n = 22) - Not included
hyperalgesia measures in
areas of were categorized
Studies included in into local and remote: n=3
quantitative synthesis
(meta-analysis)
(n = 8 )
Included

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 Figure 2. Synthesis Forest Plot PPT
Accepted Article

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 Figure 3. Heterogeneity Funnel Plot for PPT
Accepted Article

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 Figure 4. Exclusion sensitivity Plot for PPT
Accepted Article

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 Figure 5. Synthesis Forest Plot for CPT
Accepted Article

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 Figure 6. Synthesis Forest Plot for HPT
Accepted Article

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 Figure 7. Heterogeneity Funnel Plot for HPT
Accepted Article

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 Figure 8. Exclusion sensitivity Plot for HPT
Accepted Article

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