Association between temporomandibular-disorder-related pain and primary headaches : results of finnish population-based surveys

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DISSERTATIONS | JAVED ASHRAF | ASSOCIATION BETWEEN TEMPOROMANDIBULAR-DISORDER-RELATED PAIN ... | No 6

JAVED ASHRAF

Association between temporomandibular- disorder-related pain and primary headaches

—results of Finnish population-based surveys

Dissertations in Health Sciences

PUBLICATIONS OF

THE UNIVERSITY OF EASTERN FINLAND

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ASSOCIATION BETWEEN

TEMPOROMANDIBULAR-DISORDER-RELATED PAIN AND PRIMARY HEADACHES—RESULTS OF

FINNISH POPULATION-BASED SURVEYS

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Javed Ashraf

ASSOCIATION BETWEEN

TEMPOROMANDIBULAR-DISORDER-RELATED PAIN AND PRIMARY HEADACHES—RESULTS OF

FINNISH POPULATION-BASED SURVEYS

To be presented by permission of the

Faculty of Health Sciences, University of Eastern Finland for public examination in CA101 Auditorium, Kuopio

on November 5^th, 2021, at 12 o’clock noon Publications of the University of Eastern Finland

Dissertations in Health Sciences No 647

Institute of Dentistry, Faculty of Health Sciences University of Eastern Finland

Kuopio 2021

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Series Editors

Professor Tomi Laitinen, M.D., Ph.D.

Institute of Clinical Medicine, Clinical Physiology and Nuclear Medicine Faculty of Health Sciences

Lecturer Tarja Välimäki, Ph.D.

Department of Nursing Science Faculty of Health Sciences Professor Ville Leinonen, M.D., Ph.D.

Institute of Clinical Medicine, Neurosurgery Faculty of Health Sciences

Professor Tarja Malm, Ph.D.

A.I. Virtanen Institute for Molecular Sciences Faculty of Health Sciences

Lecturer Veli-Pekka Ranta, Ph.D.

School of Pharmacy Faculty of Health Sciences

Distributor:

University of Eastern Finland Kuopio Campus Library

P.O.Box 1627 FI-70211 Kuopio, Finland

www.uef.fi/kirjasto PunaMusta Oy

Vantaa, 2021

ISBN: 978-952-61-4318-7 (print) ISBN: 978-952-61-4319-4 (PDF)

ISSNL: 1798-5706 ISSN: 1798-5706 ISSN: 1798-5714 (PDF)

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Author’s address: Institute of Dentistry

University of Eastern Finland KUOPIO

FINLAND

Doctoral programme: Doctoral programme in Clinical Research Supervisors: Clinical Lecturer Tuomas Saxlin, DDS, Ph.D.

Institute of Dentistry

FINLAND

Professor Anna Liisa Suominen, DDS, Ph.D.

FINLAND

Professor Emeritus Matti Närhi, DDS, Ph.D.

FINLAND

Reviewers: Docent Jari Ahlberg, DDS, Ph.D.

Institute of Dentistry University of Helsinki HELSINKI

FINLAND

Docent Marjo-Riitta Liljeström, DDS, Ph.D.

Institute of Dentistry University of Turku TURKU

FINLAND

Opponent: Professor Thomas List, DDS, Ph.D.

Faculty of Odontology University of Malmö

MALMÖ SWEDEN

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Ashraf, Javed

Association between temporomandibular-disorder-related pain and primary headaches—results of Finnish population-based surveys

Kuopio: University of Eastern Finland

Publications of the University of Eastern Finland Dissertations in Health Sciences 647. 2021, 94 p.

ISBN: 978-952-61-4318-7 (print) ISSNL: 1798-5706

ISSN: 1798-5706

ISBN: 978-952-61-4319-4 (PDF) ISSN: 1798-5714 (PDF)

ABSTRACT

Headaches form a major comorbid condition accompanying temporomandibular- disorder-related pain (TMD-related pain). Together, these debilitating conditions pose a significant burden on the population.

This dissertation aimed to study the possible associations of two clinically assessed signs of TMD-related pain (muscle-related TMD pain [mTMD] and temporomandibular joint-related TMD pain [jTMD]) with the presence of primary headaches (migraine and tension-type headaches [TTH]) through cross-sectional (Study I) and longitudinal (Studies II & III) study designs.

The population of Study I consisted of the Health 2000 Survey participants who underwent a clinical TMD examination and answered questions related to the presence and frequency of migraine, as well as the presence of headache medication consumption, during an interview (n = 5,876). The population of the Studies II and III was taken from both the Health 2000 Survey (baseline) and the Health 2011 Survey (follow-up) including participants undergoing clinical TMD examination at baseline and answering questions about the presence of migraine and TTH at follow-up (n = 530).

Based on the multivariate, cross-sectional regression analyses, mTMD, but not jTMD was associated with the presence of migraine (Study I). The results of Study I also showed that migraine with TMD-related pain was associated with higher migraine frequency and the presence of headache medication consumption.

Based on the frequentist logistic regression analyses (Study II), no association between mTMD or jTMD at baseline and the presence of migraine at follow-up was

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observed (Study II). However, participants with mTMD at baseline had two-times higher odds for having TTH at follow-up than participants without mTMD at

baseline. Moreover, jTMD at baseline was weakly and inversely associated with the presence of TTH at follow-up. Sensitivity analyses revealed that the estimates of these regression analyses were modestly free from unmeasured confounding effects. Results of Study III (Bayesian logistic regression) suggested that neither mTMD nor jTMD at baseline were associated with the presence of migraine at follow-up. However, mTMD at baseline was associated with the presence of TTH at follow-up. No consistent association was found between jTMD at baseline and the presence of TTH at follow-up. Bayesian sensitivity analyses revealed that the estimates of these regression models were stable, demonstrating sufficient validity and consistency of the effect estimates. The results were quite consistent across different statistical methodologies, although slightly more precise with the Bayesian approach.

These results indicate that diverse mechanisms may exist behind the associations between TMD-related painful conditions and different types of primary headaches.

Keywords: Epidemiology; Pain; Temporomandibular disorders; Migraine; Tension- type headache; Bayesian statistics; Directed acyclic graphs; Sensitivity analysis

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Ashraf, Javed

Purentaelimistön toimintahäiriöihin liittyvän kivun yhteys primaaripäänsärkyihin – tuloksia suomalaisista väestötutkimuksista

Kuopio: Itä-Suomen yliopisto

Publications of the University of Eastern Finland Dissertations in Health Sciences 647. 2021, 94 s. ISBN: 978-952-61-4318-7 (nid.)

ISSNL: 1798-5706 ISSN: 1798-5706

ISBN: 978-952-61-4319-4 (PDF) ISSN: 1798-5714 (PDF)

TIIVISTELMÄ

Päänsäryt ovat tärkeä purentaelimistön toimintahäiriöihin (TMD) liittyvän kivun komorbiditeetti. Yhdessä nämä tilat muodostavat merkittävän terveystaakan väestötasolla.

Tämän väitöstutkimuksen tavoitteena oli tutkia kahden kliinisesti määritetyn TMD-kivun merkin (lihasperäinen ja leukanivelperäinen TMD-kipu) yhteyttä primaaripäänsärkyjen (migreeni ja jännityspäänsäryt) esiintymiseen.

Väitöstutkimuksessa oli sekä poikkileikkaus- (Osatyö I) että pitkittäisasetelma (Osatyöt II ja III). Ensimmäisen osatyön aineisto koostui henkilöistä, jotka osallistuivat Terveys 2000 -tutkimuksen kliiniseen TMD-tutkimukseen sekä vastasivat terveyshaastattelussa migreenin esiintymistä ja esiintymisen tiheyttä sekä migreenilääkitystä koskeviin kysymyksiin (n = 5,876). Toisen ja kolmannen osatyön aineisto koostui henkilöistä, jotka osallistuivat Terveys 2000 -tutkimuksen kliiniseen TMD-tutkimukseen sekä vastasivat migreeniä ja jännityspäänsärkyjä koskeviin kysymyksiin Terveys 2011 -tutkimuksen terveyshaastattelussa ja tarkentavassa kyselytutkimuksessa (n = 530).

Ensimmäisen osatyön tulosten perusteella lihasperäinen, mutta ei

leukanivelperäinen, TMD-kipu oli yhteydessä migreenin esiintymiseen. Tulosten mukaan TMD-kipu oli yhteydessä myös migreenin esiintymisen tiheyteen ja migreenilääkityksen käyttöön. Frekventistisen logistisen regressioanalyysin (Osatyö II) tulosten perusteella ei havaittu yhteyttä alkutilanteen TMD-kivun ja migreenin esiintymisen välillä seurannan jälkeen. Sen sijaan henkilöiden, joilla esiintyi alkutilanteessa lihasperäistä TMD-kipua, vetosuhde jännityspäänsärkyjen

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ei alkutilanteessa esiintynyt TMD-kipua. Leukanivelperäinen TMD-kipu oli käänteisesti, joskin heikosti, yhteydessä jännityspäänsärkyjen esiintymiseen.

Herkkyysanalyysien perusteella mahdollisten mittaamattomien sekoittavien tekijöiden merkitys oli kohtalaisen vähäinen. Kolmannen osatyön (Bayesiläinen logistinen regressio) tulosten mukaan alkutilanteen TMD-kipu ei ollut yhteydessä migreenin esiintymiseen seurannan jälkeen. Lihasperäinen TMD-kipu ennusti jännityspäänsärkyjen esiintymistä, mutta leukanivelperäisen TMD-kivun ja

jännityspäänsärkyjen esiintymisen välillä ei havaittu selkeää yhteyttä. Bayesiläisten herkkyysanalyysien perusteella estimaatit olivat johdonmukaiset ja validit.

Pitkittäistutkimusten tulokset olivat johdonmukaiset eri tilastomenetelmien välillä, mutta hieman tarkemmat Bayesiläisia menetelmiä käyttäen.

Tämän väitöstutkimuksen tulosten mukaan mekanismit eri TMD-kivun tyyppien ja päänsärkyjen välisten yhteyksien taustalla saattavat olla vaihtelevia.

Avainsanat: Epidemiologia; Kipu; Purentaelimistön toimintahäiriöt; Migreeni;

Jännityspäänsärky; Bayesiläinen tilastotiede; Suunnattu syklitön verkko;

Herkkyysanalyysi

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ACKNOWLEDGEMENTS

This doctoral research study was conducted at the Institute of Dentistry, University of Eastern Finland, in collaboration with the Finnish Institute for Health and

Welfare. The present study was possible only with the support and contributions of several people.

I am extremely grateful to my supervisors, Clinical Lecturer Tuomas Saxlin, DDS, Ph.D, Professor Anna Liisa Suominen, and Professor Emeritus Matti Närhi, for all the guidance and support throughout the PhD work. I am thankful to my main supervisor Tuomas Saxlin for his thought provoking questions and guidance in scientific writing. His supervision and support in my doctoral research work have been indispensable. The help and guidance of Professor Anna Liisa Suominen, the head of the Institute of Dentistry, have been instrumental in many aspects of this academic endeavor. Thank you, Professor Liisa, for introducing me to the newer topics in the field of epidemiological methodology. Also important to mention is her help during the administrative issues and the support and freedom she gave me for carrying out advanced methodological techniques in my thesis.

It has also been a great experience working with Professor Emeritus Matti Närhi since the start of this academic journey. His role as a mentor has been pivotal throughout the journey that saw many ups and downs. Professor Emeritus Matti Närhi always listened to my needs and was always there to help whenever needed in every way possible. Words will not simply be enough to thank Professor Emeritus Matti Närhi

I would like to extend my gratitude to the Finnish Institute for Health and Welfare and all the members of the Oral Health Committee for providing me with the opportunity to work with the Health 2000 Survey and the Health 2011 Survey data. I thank Researcher Tuija Jääskeläinen, Ph.D, for her help in data acquisition, and for her prompt response to queries regarding the data.

I also wish to thank Docent Jari Ahlberg, DDS, Ph.D, and Docent Marjo-Riitta Liljeström, DDS, Ph.D, for carefully reviewing this thesis. My co-author Nina Zaproudina, MD, Ph.D, is also acknowledged for her contribution to this thesis.

I am deeply grateful to my dear, always supportive wife Sobia Manzoor, who has always encouraged me to keep on going during this journey. Also, I would like to thank my children, Ubaab Zahra, Hanya Batool, and Eeman Fatima, for their patience and preseverance in living without their father for so many years. I would also wish to thank my beloved parents and sisters, for all the love, support,

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prayers, and encouragement. I have eagerly awaited the finishing point of this research work, and I hope that they can all take pride and acknowledgement in this achievement.

I am fortunate to have had the support and encouragement from my respected dear friends and fellow colleagues during these past years of my doctoral research work. I would also like to express my gratitude to the Faculty of Health Sciences, University of Eastern Finland, the Finnish Dental Society Apollonia, and the

Minerva Foundation, Helsinki, for their financial support during this research work.

I am particularly grateful to the Institute of Dentistry, University of Eastern Finland, where I have had the privilege of working as an early-stage researcher.

Kuopio, September 2021 Javed Ashraf

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LIST OF ORIGINAL PUBLICATIONS

This dissertation is based on the following original publications:

I

II

Ashraf J, Zaproudina N, Suominen A L, Sipilä K, Närhi M and Saxlin T.

Association between temporomandibular disorders pain and migraine: results of the Health 2000 Survey. Journal of Oral & Facial Pain and Headache 33: 399- 407, 2019. DOI: 10.11607/ofph.2213.

Ashraf J, Närhi M, Suominen A L, Zaproudina N and Saxlin T.

Temporomandibular-disorder-related pain as a predictor of severe

headaches. Community Dentistry and Oral Epidemiology: 2021. DOI: 10.1111/

cdoe.12654. Online ahead of print.

III Ashraf J, Närhi M, Suominen A L and Saxlin T. Association of

temporomandibular-disorder-related pain with severe headaches—A Bayesian view. Clinical Oral Investigations: 2021. DOI: 10.1007/

s00784-021-04051-y. Online ahead of print.

The publications were adapted with the permission of the copyright owners.

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ABBREVIATIONS

ANA Anti-nuclear antibody BRIF Bioresource research

impact factor

CA Cutaneous allodynia CI Confidence interval CrI Credible interval CSD Cervical spine

dysfunction DAG

DC/TMD

Directed acyclic graph Diagnostic criteria for temporomandibular disorders

GWAS Genome-wide association studies jTMD TMD-related

temporomandibular joint pain;

Temporomandibular joint pain as a sign of temporomandibular disorders

mTMD TMD-related muscle pain; Masticatory muscle pain as a sign of temporomandibular disorders

OR Odds ratio OSA Obstructive sleep

apnea

PPT Pressure pain threshold

RDC/TMD Research diagnostic criteria for

Temporomandibular Disorders

RF Rheumatoid factor TMD Temporomandibular

disorders

TMJ Temporomandibular joint

TrP Myofascial trigger point TTH Tension-type headache U.S. United States of

America

YLD Years lost due to disability

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1 INTRODUCTION

Temporomandibular disorders (TMD) affect a sizeable proportion of the global population. A recent systematic review indicated that the prevalence of having at least one clinical sign of TMD ranges between 5 to 60% in global population (Ryan et al., 2019). Of these clinical signs, pain in the temporomandibular region is common, occurring in approximately 10.0% of the adult population (Al-Jundi et al., 2008). A recent Finnish study reported that more than one-third (34.3%) of the Finnish adult population experienced at least one clinical sign of TMD. The same study also reported that the prevalence of TMD-related muscle pain (mTMD) was 1.9% and 6.5% for males and females, respectively. The prevalence of TMD-related temporomandibular joint pain (jTMD) accounted to 1.7% and 3.5% for males and females, respectively (Qvintus et al., 2020). This high TMD-related pain prevalence renders it a significant public health problem globally as well as in Finland.

Primary headaches, which mainly comprise migraine and tension-type headaches (TTH), form the second leading cause of years lost due to disability (YLD), after lower back pain, affecting more than three billion individuals globally.

Additionally, the number of persons suffering from headaches globally increased by 15.5% from the year 2007 to 2017. The number of individuals suffering from migraine and TTH worldwide in the year 2017 was estimated to be 1.3 and 2.3 billion, respectively. The percentage increase in the number of individuals

suffering from these disorders for the decade of 2007–2017 was 15.3% and 15.6%

for migraine and TTH, respectively (James et al., 2018). In the Finnish population—

according to a recent retrospective study based on the electronic medical records of Finland’s largest private occupational health care provider—7.0% of females and 2.0% of males suffered from migraine (Korolainen et al., 2019). Moreover, the percentage of people suffering from TTH in Finland amounted to 16.0% of the total population (Raggi and Leonardi, 2015).

Isolated cases of TMD-related pain occur in approximately 17.0% of the TMD- related pain population (Plesh et al., 2011); usually some other painful condition accompanies TMD-related pain. TMD-related pain is often associated with other chronic pains—headaches, neck, back, and joint pain—causing significant physical and psychological disability (Rantala et al., 2003). Amongst the co-morbidities of TMD-related pain, headaches are most frequently reported along with mTMD and jTMD (List and Jensen, 2017). These co-morbidities may sometimes be interpreted as a single entity by patients (Speciali and Dach, 2015).

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Evidence suggests that current treatments indicated for TMD-related pain and primary headaches may be beneficial for the treatment of both conditions (Goncalves et al., 2012; Conti et al., 2016; Hara et al., 2016). However, although cross-sectional association of TMD-related pain with the presence of primary headaches has been reported (Goncalves et al., 2011; Bevilaqua et al., 2009), longitudinal evidence regarding the prognosis and potential long-term predictors of primary headaches is still scarce (Probyn et al., 2017). Few prospective studies exist examining the association of TMD-related pain with primary headaches.

Considering the existing knowledge gaps regarding the association between TMD-related pain and the presence of primary headaches, the current thesis aimed to investigate the association of TMD-related pain with primary headaches

—namely migraine and TTH—at both cross-sectional and longitudinal levels. Data for these studies were taken from the Finnish nationally representative Health 2000 and Health 2011 Surveys (Bio-Resource Impact Factor [BRIF] 8901). TMD- related pain variables (from the Health 2000 Survey) were used as predictors in all studies. The presence of migraine (from the Health 2000 Survey) was

considered as the main outcome variable in the cross-sectional investigation, while the two longitudinal studies utilized both the presence of migraine and the presence of TTH (from the Health 2011 Survey) as the outcome variables.

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2 REVIEW OF THE LITERATURE

TEMPOROMANDIBULAR-DISORDER-RELATED PAIN

TMD is the most common orofacial pain condition, encompassing the pain and dysfunction of the masticatory muscles and TMJs collectively (Ryan et al., 2019).

Clinical features of TMD include regional pain in the face and preauricular area (including masticatory muscles), limitations in the jaw movements, and sounds (clicking and crepitation) from the TMJs during jaw movements (List and Jensen, 2017). According to the literature, approximately half of the population has suffered from at least one symptom of TMD (Gesch et al., 2004; Bonjardim et al., 2009; Goncalves et al.,2010; Monteiro et al., 2011; De Mello et al., 2014; Minghelli et al., 2014; Wieckiewicz et al., 2011). A recent Finnish study reported that around one third of the Finnish adult population had at least one clinical sign of TMD (Qvintus et al., 2020).

TMD-related pain, on the other hand, was reported to occur in approximately 10% of the global adult population (Leresche, 1997; Al-Jundi et al., 2008). The range of the Finnish adult population reporting TMD-related pain varied between 2–19%, depending on the type and location of the pain, and the gender of the study participant (Rutkiewicz et al., 2006). However, a recent Finnish study reported that more than one-third (34.3%) of the Finnish adult population experienced at least one clinical sign of TMD. This study also reported that the mTMD accounted for 1.9% and 6.5% in male and female populations, respectively. The prevalence of jTMD, on the other hand, was 1.7% and 3.5% in males and females, respectively (Qvintus et al., 2020). A recent systematic review reported that the prevalence of signs and symptoms of TMD-related pain in the general population varied greatly from one study to another, ranging from 1–75% when established on clinical evaluations and 6–75% when based on pain questionnaires only (Ryan et al., 2019).

This diversity may be due to different methodologies and diagnostic criteria employed in the various studies (Manfredini et al., 2010; Unell et al., 2012).

Additionally, these differing prevalences of reported TMD signs and symptoms may be attributed to the heterogeneity in the studies’ populations, and the selection criteria employed in the studies (Ryan et al., 2019).

Variation in TMD-related pain symptoms occurs due to factors such as age, gender, and ethnic background of the patients. Orofacial Pain: Prospective

Evaluation and Risk Assessment (OPPERA), a United States (U.S.) multicenter study,

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reported that the first-onset TMD-related pain developed at a rate of nearly 4.0%

of people per annum in this U.S. community-based cohort of 18 to 44-year-olds.

Results of the OPPERA also revealed that age was (inversely) associated with an increased incidence of TMD-related pain, whereas females reported slightly greater incidence than males. Also, compared to Caucasians, African Americans had greater incidence and Asians had lower incidence of TMD-related pain (Slade et al., 2013).

EVOLUTION OF THE DIAGNOSTIC CRITERIA FOR

TEMPOROMANDIBULAR DISORDERS SIGNS AND SYMPTOMS

The diagnostic criteria of the clinical signs of TMD have evolved over the last three decades. The first attempt at an evidence-based diagnostic approach for TMD emerged in 1992 and was known as the Research Diagnostic Criteria for

Temporomandibular Disorders (RDC/TMD). RDC/TMD emerged from the need for a diagnostic system that could reliably distinguish the presence of TMD for, not only epidemiological, but also clinical research purposes (Dworkin and LeResche, 1992) (Table 1). For the next two decades of its operationalization (the 1990s–

2010s), the RDC/TMD was regarded as the standard diagnostic criteria employed in clinical practice and most TMD-related peer-reviewed scientific publications.

However, the need for a critical assessment of the RDC/TMD was recognized by the National Institute of Dental and Craniofacial Research, which funded the multisite Validation Project to assess its reliability and validity. This project not only retained all the operational principles and definitions foundational to the

RDC/TMD, but also improved them where possible (Ohrbach and Dworkin, 2016).

Nevertheless, despite finding excellent reliability coefficients, kappa scores, for the RDC/TMD criteria implemented TMD examination, the Validation Project report also uncovered some shortcomings in the criteria. The concluding report of the Validation Projectstated that the RDC/TMD-specified clinical examinations as a stand-alone criterion of diagnosis for TMD were prone to diagnostic

misclassifications of the disease. This shortcoming advocated for the use of radiographic techniques for better diagnostic validity (Look et al., 2010). However, the inclusion of a radiographic procedure as a diagnostic aid in a population-level study remains a significant limitation.

Future research in TMD examination necessitates updated and scientifically advanced diagnostic criteria. The DC/TMD (Diagnostic Criteria for

Temporomandibular Disorders) has now replaced the old RDC/TMD and is

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recommended for use in the research and clinical examinations. Advantages of DC/TMD over RC/TMD include a better and more accurate diagnosis, which takes into consideration both the patients’ reported symptoms, and the clinical signs found in the examination. This adds significantly to RDC/TMD, which relied solely on the signs observed during examinations diagnosing mTMD and jTMD.

Furthermore, DC/TMD employs a more extensive report of the TMD patients’

symptoms, especially pain and the psychosocial aspects (compared to Axis II of the RDC/TMD criteria). Also, DC/TMD provides an important reference in the diagnosis of TMD-related headaches. Another point of particular significance is the fact that the DC/TMD criteria uses the past 30 days as a reference when asking the patient about their symptoms. This precise timeframe is of importance in fluctuating conditions like TMD-related pain and headaches. All of these advantages render DC/TMD a broader and more accurate criterion compared to RDC/TMD in several aspects (Ohrbach et al., 2013; Ohrbach 2016). Summarily, if DC/TMD is utilized more extensively in future research; it will generate more valid and comprehensive information resulting in more comparable and replicable studies. In Finland, DC/TMD criteria is now a part of the curriculum at all the universities.

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Table 1. Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) (Dworkin and LeResche, 1992).

Axis Diagnosis Subtypes

I Muscle Disorders a) Myofascial pain

b) Myofascial pain with limited opening II Disk Displacement a) Disk displacement with reduction

b) Disc displacement without reduction, with limited opening

c) Disc displacement without reduction, without limited opening

III Arthralgia, Osteoarthritis, Osteoarthrosis

a) Osteoarthritis of the TMJ

b) Osteoarthrosis of the TMJ

ETIOLOGY OF TEMPOROMANDIBULAR-DISORDER-RELATED PAIN

The precise etiology of TMD-related pain has been a center of debate for a long period. Most scientists in the field have proposed a multifactorial causation for TMD-related pain. The multifactorial etiology has been attributed to psychological stress (Reiter et al., 2015), age (Manfredini et al., 2010), gender (Robinson et al., 2020), occlusion (De Kanter et al., 2018), oral parafunction (Slade et al., 2016), sleep disorders (Wu et al., 2020), and genetics (Smith et al., 2011). Furthermore,

nonspecific inflammatory autoimmune factors have also been implicated in the etiology of TMD-related pain (Kim et al., 2018).

It has been reported in the literature that psychosocial factors form a vital etiological component of TMD-related pain and its severity (Bonjardim et al., 2009;

Wieckiewicz et al., 2014; Reiter et al., 2015). Evidence suggests higher levels of depression and anxiety in TMD-related pain patients compared to individuals not experiencing TMD-related pain (Ryan et al., 2019). It has also been reported that emotional stress or feelings of anxiety increase masticatory muscle activity leading to teeth clenching resulting in circulatory changes in the muscles, ultimately predisposing to TMD-related pain (Lajnert et al., 2010). Another study suggested that the frequent use of anti-depressants, such as selective serotonin reuptake inhibitors, might contribute to muscle pains such as in mTMD. The same study also reported development of bruxism—a known TMD risk factor, defined as a

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repetitive masticatory-muscle activity characterized by clenching or grinding of the teeth and/or by thrusting forward of the mandible (Lobbezoo et al., 2013)—with constant anti-psychotic drug usage (Amir et al., 1997).

Age might not be of direct etiological significance for TMD-related pain.

However, a study by Manfredini et al. (2010) reported two distinct age groups based on the symptoms of TMD. The younger age group (mean age 32.7 years) sought TMD advice mostly due to pain and/or clicking sounds in the TMJs, while the older age group (mean age 54.2 years) often sought physician help due to inflammatory degenerative disorders of the TMJs (Manfredini et al., 2010). These findings may show that age is an important factor in determining the etiological picture of TMD pathology.

Twice as many women suffer TMD-related pain compared to men (Bueno et al., 2018). One possible explanation for the increased prevalence of TMD-related pain in females might be attributed to variations in estrogen levels. Results from the recent European and U.S. studies suggest that inconsistent levels of estrogen may perpetuate certain types of TMD—especially TMD-related pain (mTMD and/or arthralgia [jTMD])—in the menopause transition phase occurring at age 45–55 (Lövgren et al., 2016; Maixner et al., 2016). Another study reported that TMJ degeneration increased in women over the age of 50 causing degenerative TMD problems such as osteoarthritis (Guarda-Nardini et al., 2012). Based on the results of the studies, it may be hypothesized that estrogen has a biphasic effect on TMD, with high and/or fluctuating estrogen levels promoting certain types of TMD- related pain, and low levels of estrogen potentiating other types of TMD-related pain (Robinson et al., 2020).

The association between TMD-related pain and occlusion has not been defined in terms of causal certainty. The reasons may be attributable to various distinct and diverse definitions of both TMD and occlusion from various perspectives (De Kanter et al., 2018). A systematic review of population-based studies reported inconsistent associations between malocclusions and TMD-related pain (Gesch et al., 2004). Additionally, an epidemiological survey of adults reported similar results, with identified associations between malocclusions and clinical signs of TMD- related pain being few and inconsistent (Gesch et al., 2005).

As mentioned above, also oral parafunctional habits, such as bruxism, has been suggested to have a role in the onset of TMD-related pain. However, based on the findings of a recent systematic review, the strength of the association between bruxism and TMD-related pain is inconsistent (Manfredini et al., 2011). The OPPERA study found that oral parafunctional habits were a strong predictor of

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TMD-related pain. The OPPERA study also mentioned that the parafunctional behavior in initially TMD-related pain-free participants may suggest some form of central dysregulation—such as heightened motor activation or reduced

proprioception—leading to TMD-related pain initiation (Slade et al., 2016).

Several studies have reported an association between TMD-related pain and sleep disorders (Smith et al., 2009; Sanders et al., 2013; Slade et al., 2013). A variety of mechanisms has been postulated in the pathogenesis of TMD-related pain due to obstructive sleep apnea (OSA) (Talley, 2019). Firstly, poor or disturbed sleep patterns in OSA patients might increase pain sensitivity, contributing to hyperalgesia, an important feature of TMD-related pain pathology (Bair et al., 2016). Secondly, OSA patients often exhibit chronic intermittent hypoxemia, which increases the levels of inflammatory cytokines, possibly contributing to the

pathogenesis of TMD-related pain (Dewan et al., 2015). Indeed, studies have reported higher systemic levels of inflammatory cytokines both in OSA and TMD- related pain (Park and Chung, 2016; Doufas et al., 2013) corroborating the hypothesis that OSA might contribute to the pathogenesis of TMD-related pain through enhancing systemic inflammation. Thirdly, OSA patients may have craniofacial structural and/or muscle dysfunctions that may predispose them to the development of TMD-related pain (Wu et al., 2020).

Recent evidence also suggests the potential role of autoimmunity in the

pathogenesis of TMD-related pain. Biomarkers such as antinuclear antibody (ANA) and rheumatoid factor (RF) have been found to enhance the pain levels of the TMD-related pain population. ANA and RF positivity may thus worsen the functional problems among these subjects (Kim et al., 2018).

Lastly, a case-control study conducted as a part of the OPPERA study suggested that TMD-related pain has a strong genetic predisposition. The study by Smith et al. (2011) revealed that TMD has numerous genetic risk factors including genes such as HTR2A, COMT, NR3C1, CAMK4, CHRM2, IFRD1, and GRK5 (Smith et al., 2011). Diagrammatic representation of the TMD-related pain etiology is presented in Figure 1

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Figure 1. Diagrammatic representation of the risk factors and pathophysiology of temporomandibular-disorder-related pain (TMD-related pain).

PUBLIC HEALTH SIGNIFICANCE OF TEMPOROMANDIBULAR- DISORDER-RELATED PAIN

TMD-related pain poses a significant public health burden on the global population. Several cross-sectional studies have reported that the overall prevalence of TMD-related pain is significantly higher in the 20–45 age group compared with other age groups (Goncalves et al., 2010; Balke et al., 2010;

Yekkalam et al., 2014). It is pertinent to mention that women suffer 1.5 to 2 times more from the symptoms of TMD-related pain compared to males (Dworkin et al., 1990). This age range can be regarded as the reproductive period of females, both in terms of their work and family lives (LeResche et al., 2003). Therefore, a high prevalence of TMD-related pain in this age group assigns it a unique public health importance, both in terms of productivity and contributions to work and society.

Another significant public health impact of pain on population, in general, is its association with psychological factors, such as increased anxiety and depression

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(Vadivelu et al., 2017). Consequently, the concurrence of TMD-related pain along with psychological factors might add to the further deterioration in work–life capacities, adding to the public health burden of the population. Recent literature suggests that there has been an increasing trend in TMD prevalence in the general population over recent decades (Ryan et al., 2019). However, recognizing a sign of TMD, such as TMD-related pain, at an early stage may allow early intervention to avoid further complications. This early recognition may significantly aid in avoiding or at least minimizing the magnitude of TMD-related disability in adulthood.

PRIMARY HEADACHES

Headaches are categorized into primary headaches (occurring without any

recognized cause) and secondary headaches (occurring due to a recognized cause) (Levin, 2013). Migraine, TTH and cluster headaches make up the significant portion of primary headaches (Straube and Andreou, 2019). International Classification of Headache Disorders 3 (ICHD-3) dictates that the classification of headache

disorders now and in the future will only be evidence based. The ICHD-3

classification is hierarchical in nature. A distinct feature of ICHD-3 classification is the liberty it imparts to the investigator in terms of diagnostic details envisioned for the planned study. The ICHD-3 employs a five-point range system for

classification. The first point forms an impression as to which group the patient belongs to, for example: 1. Migraine or 2. Tension-type headache or 3. Trigeminal autonomic cephalalgias, etc. In most epidemiological settings, only the first- or second-digit diagnoses are usually applied, whereas in specialist practice and headache centers a diagnosis at fourth- or fifth-digit levels is usually used.

Of particular interest in ICHD-3 is the criteria defining Headaches attributed to temporomandibular disorders (coded as criterion 11.7 of ICHD-3). These criteria are a very useful tool in validly defining the headaches arising due to a disorder involving structures in the temporomandibular region. The criteria 11.7 of the ICHD-3 provides clinical evidence of a painful pathological process affecting elements of the temporomandibular joint(s), muscles of mastication and/or associated structures on one or both sides. The fulfillment of the criterion11.7 of the ICHD-3 requires presence of at least two of the following three attributes 1) the headache has developed in temporal relation (occurring after discovery of TMD) to the onset of TMD, or led to its discovery, 2) the headache is exacerbated by jaw motion, jaw function (e.g. chewing) and/or jaw parafunction (e.g. bruxism), 3) the headache is initiated on the physical examination (palpation) of the

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temporalis muscle and/or passive movement of the jaw (https://ichd-3.org).

Population-based neuroepidemiological studies represent an accurate method of estimating the true incidence and prevalence of various neurological disorders, including headaches (Woldeamanuel and Cowan, 2017). Headache disorders comprise the most common disorders of the nervous system and are included in the top ten reasons of disability worldwide (WHO, 2016). Headache disorders are the second leading cause of YLD after lower back pain, and it has been estimated that migraine and TTH affect more than three billion individuals worldwide.

Moreover, the percentage increase in the number of individuals suffering from migraine and TTH for the decade 2007–2017 was 15.3% and 15.6%, respectively (James et al., 2017).

Migraine is a debilitating and progressive disease that has been reported in different clinical contexts (Gonçalves et al., 2011; Chaves et al., 2016; Carvalho et al., 2016). According to the U.S. National Institute of Neurological Disorders and Stroke (NINDS), migraine is described as an intense pulsating or throbbing pain in one side of the head. The International Headache Society (IHS) diagnoses a migraine by its pain, frequency (at least five episodes per month, lasting 4–72 hours if untreated), and additional symptoms including nausea and/or vomiting, or sensitivity to both light and sound (Nih.gov, 2010). The number of individuals suffering from migraine in the year 2017 was estimated to be 1.33 billion (James et al., 2017). Furthermore, according to a recently published meta-analysis and systematic review, the global migraine prevalence was reported as 11.6%, while in the different continents it was reported as 10.4% in Africa, 10.1% in Asia, 11.4% in Europe, 9.7% in North America, and 16.4% in Central and South America. When this population cohort was stratified, the global prevalence of migraine was noted as 13.8% among females, 6.9% among males, 11.2% among urban residents, 8.4%

among rural residents, and 12.4% among school and college students (Woldeamanuel and Cowan, 2017).

TTH represents repetitive episodes of headache, which may last from minutes to weeks. TTH pain is usually felt as a tight band around the head of mild to moderate intensity and bilateral in location. TTH pain is not aggravated by routine physical activity and is not accompanied by nausea or vomiting. However,

photophobia or phonophobia may occasionally be present with TTH. TTH is generally considered an ordinary headache due to its self-limiting nature.

However, in comparison to the acute episodes of TTH, chronic forms of TTH are regarded as a greater source of distress and discomfort and hence their sufferers are referred more frequently for medical help (Jensen, 2018). TTH are the most

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prevalent headaches globally (Jensen et al., 2008). The number of individuals suffering from TTH in the year 2017 was estimated to be 2.33 billion (James et al., 2017). A Danish population-based study reported the lifetime prevalence of TTH as 78%, but upon further stratification, it was observed that a vast majority, 59%, had episodic TTH and hence were not in need of any medical care (Lyngberg et al., 2005).

Cluster headaches are characterized by severe, unilateral pain episodes lasting between 15 minutes to several hours. Cluster headaches are usually accompanied by autonomic symptoms such as lacrimation and conjunctival hyperemia (May et al., 2018). Fortunately, cluster headaches occur in only approximately 0.5% of the population. Although considered rare, in the U.S. approximately 150,000

individuals are diagnosed as cluster headache sufferers annually (Gross, 2006).

An important point to mention regarding headache symptomology is its fluctuating nature. The type of headaches has been shown to evolve in time, in children, adolescents and in adults alike (Dao and Qubty 2018). This fact should be given due consideration, especially when comparing the results between different studies. The differences between criteria become particularly important when different timeframes regarding the onset of headaches are employed (usually between past threemonths to one’s lifetime). Use of such large ranges of time period may create significant bias in results, considering the overlapping of the headache types during different life periods.

ETIOLOGY AND PATHOPHYSIOLOGY OF PRIMARY HEADACHES

Primary headaches are caused due to a problem in the pain-sensitive structures of the head and neck region, and thus do not represent a symptom of an underlying disease (Rizzoli and Mullally, 2018). Migraine is a complex disease with multiple factors contributing to its etiology. These factors can be broadly classified as environmental (Levy et al., 2009), hormonal (Craft, 2007), and genetic (Sutherland and Griffiths, 2017). Environmental factors such as emotional disturbances, bright lights, sleep issues, physical exertion, and food and drink products have all been reported as triggers of migraine (Levy et al., 2009, Kelman, 2007). Estrogen has been shown to play a modulatory role in the development, initiation, and

exacerbation of migraine. This has been evident in situations of abrupt withdrawal of estrogen, which may precipitate a migraine attack, as observed in women suffering from menstrual or menopausal migraine (Craft, 2007).

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Genetically,migraine is characterized as a polygenic aberration with multiple genes contributing to disease development. A meta-analysis of genome-wide association studies (GWAS) with 59,674 cases and 316,078 controls identified 38 genomic loci to be associated with the presence of migraine (Gormley et al., 2016). However, a recent multicenter GWAS (adding to the sample size of the meta-analysis of Gormley et al. [2016) of 102,084 migraine cases and 771,257 controls identified 123 loci of which 86 are novel. A vast majority of these genomic footprints among migraine-associated variants were found on both vascular and central nervous system tissue/cell types. The genetic evidence thus supports the notion that migraine can be categorized as a disease of neurovascular nature (Hautakangas et al., 2021). An understanding of migraine through genetic factors has greatly contributed to a deeper comprehension of the mechanisms involved in the pathogenesis of the disease (Persico et al., 2015).

The pathophysiology of migraine is not fully understood, but it is believed that an activation of the trigeminovascular system causes the initiation of a migraine attack (Olesen et al., 2005). Reported pain mechanisms of migraine include cutaneous allodynia (CA) and the sensitization of neurons in the trigeminocervical complex (Bevilaqua-Grossi et al., 2010). Some of the mechanisms underlying estrogenic modulation of migraine include estrogen receptor-mediated increase in nitric oxide in vascular endothelial cells causing vasodilation and altered serotonin receptor signaling (Brandes, 2006). Serotonin receptors are important therapeutic targets in the acute treatment of migraine; serotonin agonists, such as triptans, have been utilized to relieve the symptoms in the acute phase (Craft, 2007;

Paredes et al., 2019). Diagrammatic representation of the risk factors and pathophysiology of migraine are presented in Figure 2.

The exact underlying cause of TTH is uncertain; however, activation of

hyperexcitable peripheral neurons in the head and neck musculature may be the most favored explanation. Abnormalities in central pain processing—added with generalized increased pain sensitivity—are often seen in TTH patients (Loder and Rizzoli, 2008). Genetic susceptibility to TTH has also been ascribed, and evidence suggests that chronic TTH is caused partly by genetic factors (Russell, 2007). Lastly, psychological factors such as anxiety, depression (Yücel et al., 2002), and

emotional stress (Cathcart et al., 2010) may also play an important role in the initiation and progression of TTH from the episodic to chronic phase.

Regarding TTH, a debate exists between the role of peripheral myofascial mechanisms and central brain mechanisms in its pathogenesis. Usually, both the peripheral and central mechanisms are inter-mingled in the TTH population (Yu

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and Han, 2014). Increased pericranial muscle tenderness may be attributed to inflammatory reaction, decreased blood flow (Ashina et al., 2002), increased muscle activity (Sohn et al., 2013), and muscle atrophy (Fernández-de-las-Peñas et al., 2007). Usually central sensitization—defined as a dysregulation of the central nervous system, causing neuronal hyperexcitability, and resulting in

hypersensitivity to both harmful and nonharmful stimuli—follows constant

nociceptive inputs from pericranial muscles (Neblett et al., 2013). It is believed that peripheral mechanisms usually play an important role in episodic TTH, while central mechanisms play an important role in chronic TTH. Consequently, sensitization of the central nervous system at both the supraspinal level and the spinal dorsal horn/trigeminal nucleus is observed in chronic TTH patients (Yu and Han, 2014). The updated pain model of TTH suggests that referred pain from active myofascial trigger points (TrP) in the pericranial muscles mediates the pain through the spinal cord and the trigeminal nucleus caudalis, thus sensitizing the central nervous system (Fernández-De-Las-Peñas and Schoenen, 2009). TrPs are painful spots in a stiff band of a skeletal muscle that are tender on stimulation and give rise to a referred pain (Simons et al., 1999). Present evidence thus suggests that pressure pain hypersensitivity and pericranial muscle tenderness might be a contributing but not a causative factor of chronic TTH, which may be produced by a central nervous system dysfunction (Yu and Han, 2014). Diagrammatic

representation of the risk factors and pathophysiology of TTH are presented in Figure 3.

Commonly reported risk factors for cluster headaches include alcohol consumption, warmth, stress, high altitude, and abrupt changes in weather.

Additionally, genetic factors have also been implicated in the etiology of cluster headaches (May et al., 2018). The pathophysiology of cluster headaches is not fully understood. These headaches are often referred to as trigeminal cephalic

dysfunctions (involving divisions of the trigeminal nerve that innervates the cranial blood vessels). The pathophysiology of cluster headaches involves alterations in both the central and peripheral nervous systems. These include activation of both the trigeminovascular and the parasympathetic nervous systems. These systems play an important role in the pain and autonomic parts of cluster headaches pathology, respectively. Another feature of cluster headaches is the involvement of the hypothalamus, which plays the important role of interaction with the

trigeminovascular system (May et al., 2018).

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Figure 2. Diagrammatic representation of the risk factors and pathophysiology of migraine.

Figure 3. Diagrammatic representation of the risk factors and pathophysiology of tension-type headaches (TTH).

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PUBLIC HEALTH SIGNIFICANCE OF PRIMARY HEADACHES

Evidence from the recent literature and global reports suggest that primary headaches are following an upward trend in their global prevalence (James et al., 2017; Woldeamanuel and Cowan, 2017). Subsequently, the continually increasing prevalence of primary headaches poses a significant public health challenge.

The high prevalence of migraine correlates with multiple factors. Unhealthy lifestyle patterns, such as low level of physical activity and sleep dysregulation, can lower the threshold for migraine attacks (Woldeamanuel and Cowan, 2017). The higher migraine prevalence in the European Union could be due to a combination of multiple factors, including but not limited to, inadequate attention and

prioritization given to public health policy changes regarding awareness of headaches and their management. Additional shortcomings include suboptimal headache care resource utilization and ineffective strategies, coupled with unhealthy lifestyle practices. These oversights accumulatively pose a burden on the public health systems of society (Diener et al., 2006). Tackling the increasing prevalence of primary headaches thus requires public health policy changes, as well as the participation of interdisciplinary teams at diverse and distinct domains, with active involvement at both the governmental and community levels (Bosu, 2014).

Regarding TTH, associations have been reported between chronic TTH and poor self-rated health, an inability to relax after work, and sleeping fewer hours per night. The associations between chronic TTH and various behavioral issues have a detrimental impact on the productivity of individuals suffering from TTH, signifying its public health importance. Fortunately, the overall prognosis of TTH is reasonably favorable. In a 12-year follow-up study of the general Danish

population, Lyngberg et al. (2005) found that 47% of study participants with chronic TTH experienced remission, while 12% of the cases of episodic TTH transformed into chronic TTH (Lyngberg et al., 2005).

Another aspect of the public health importance of primary headaches is the impact of its increased disease load and frequency on the quality of life of the patients. This necessitates the need for the diagnosis (recognition) and management of primary headaches in the early phases of life, i.e., during

childhood and adolescence. This may significantly lessen the burden and impact of primary headaches in the more productive adult stages of life.

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CO-MORBIDITIES ASSOCIATED WITH

TEMPOROMANDIBULAR-DISORDER-RELATED PAIN

TMD-related pain seldom occurs without any other co-morbidity. A nationally representative study in the U.S. reported that only 16.9% of TMD-related pain occurred in isolation (Plesh et al., 2011). Usually, another painful condition accompanies TMD-related pain, including chronic conditions such as headaches and neck, back, and joint pains (Rantala et al., 2003; De Laat et al., 1998; Wiesinger et al., 2007; Ballegaard et al., 2008; Sipilä et al., 2011). The co-morbidities

associated with TMD-related pain can also be classified based on the nature of the painful conditions such as regional (e.g. Cervical Spine Dysfunction [CSD]),

generalized (e.g. fibromyalgia) and local/referred (e.g. headaches) (Figure 4) (Costa et al., 2017).

Figure 4. Simplified illustration of common painful comorbidities associated with temporomandibular disorders (Costa et al., 2017). Adapted with the permission of the copyright owner.

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2.8.1 Temporomandibular-disorder-related pain and regional pain conditions The association between TMD-related pain and regional pain conditions, such as CSD, has usually been investigated from three different perspectives. These include a radiographic- and photographic-image-aided craniocervical posture analysis, electromyography-, thermography- and ultrasonography-aided analyses of cervical muscles, and musculoskeletal pain perception with the aid of various techniques, such as digital palpation, and assessment of pressure pain thresholds (PPT) (Costa et al., 2017).

Evidence suggests that patients with TMD-related pain often experience neck pain and that it is associated with a higher number of painful sites—cervical muscle TrPs and a large area of referred pain in the cervical region (Fernández-De- Las-Peñas et al., 2010). The literature also reported that patients with CSD have a decreased PPT of the masticatory muscles (La Touche et al., 2010). These findings suggest a bidirectional association between TMD-related pain and CSD.

Regarding prospective evidence, a large population-based study conducted in the U.S. reported that areas around the neck painful upon palpation are a significant risk factor for the first incidence of TMD (Ohrbach et al., 2013). The application of cervical spine physiotherapy in TMD-related pain patients was reported to increase the PPT of the masticatory muscles (La Touche et al., 2009; La Touche et al., 2013). Studies have also attempted to describe the association between TMD-related pain and CSD using a pathophysiological explanation. The association between TMD-related pain and CSD has also been explained through various mechanisms, such as central sensitization (Woolf, 2011), and neuronal convergence of the trigeminal and cervical spine regions (Mørch et al., 2007) 2.8.2 Temporomandibular-disorder-related pain and generalized pain

conditions

In addition to the association with the local and regional co-morbidities,

generalized conditions have also been reported to be associated with TMD-related pain, including fibromyalgia (Fraga et al., 2012; Gui et al., 2013). Fibromyalgia is a rheumatic disorder characterized by diffuse musculoskeletal chronic pain and multiple painful areas throughout the body, known as tender points (Wolfe et al., 1990). Fibromyalgia is common in middle-aged women (30 to 50 years) (Queiroz, 2013); thus, it resembles the pattern of prevalence of TMD-related pain (Yekkalam and Wänman, 2014).

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The first reported association between TMD and fibromyalgia dates to the late 1980s when a study indicated that 75% of patients with fibromyalgia also had a clinical history of TMD (Eriksson et al., 1988). Subsequently, extensive evidence suggested an association between TMD-related pain and fibromyalgia (Fraga et al., 2012; Gui et al., 2013). Given the evidence, it is likely that TMD-related pain might be a part of a broader pain spectrum. The scope of TMD-related pathogenesis thus necessitates a multidisciplinary approach in managing patients experiencing both TMD-related pain and fibromyalgia.

2.8.3 Temporomandibular-disorder-related pain and local/referred pain conditions

The association between TMD-related pain and headache disorders can be regarded as a local or referred pain co-morbidity due to the close anatomical proximity between the structures related to both conditions (Costa et al., 2017).

This association has been reported by studies utilizing different methodologies, including cross-sectional, cohort, and randomized controlled trials (Gonçalves et al., 2011; Costa et al., 2016; Tchivileva et al., 2017). Each of the methodological designs has provided important information for understanding this co-morbid relationship (Gonçalves et al., 2010), which will be addressed more thoroughly in the following chapter.

The DC/TMD criteria provides a detailed description of an accurate and valid diagnosis for TMD-related headaches. It includes a detailed inquiry relating to the history of experiencing headaches that include pain in the temporomandibular area supplemented by the questions relating to masticatory functions and related parafunctions. Also, adding to this inquiry, a detailed examination is performed to confirm the diagnoses of the TMD-related headaches (Ohrbach et al., 2013;

Ohrbach, 2016).

ASSOCIATION BETWEEN TEMPOROMANDIBULAR-DISORDER- RELATED PAIN AND PRIMARY HEADACHES

In general, it has been reported that the association between TMD-related pain and primary headaches is dependent on multiple temporomandibular factors, such as the nature (mTMD or jTMD), duration and severity of TMD-related pain (Goncalves et al., 2009). The more severe the symptoms of TMD-related pain, the stronger the association may be (Gonçalves et al., 2011).

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TMD-related pain and migraine are often characterized as central sensitization syndromes. The hyperexcitability in the processing of nociceptive afferents has been suggested as the main pathophysiological link between TMD-related pain and migraine (Mørch et al., 2007; Burstein et al., 2017). The association between TMD-related pain and migraine has been reported in different pathophysiological contexts (Gonçalves et al., 2011; Chaves et al., 2016; Carvalho et al., 2016). These aspects of different physiological explanations suggest that both TMD-related pain and migraine share similar pain mechanisms, including CA and the sensitization of neurons in the trigeminocervical complex (Bevilaqua-Grossi et al., 2010). Evidence suggests that although TMD-related pain and migraine are distinct conditions, both are involved in the aggravation or sustenance of the other (Pinto Fiamengui et al., 2013). This mutual pathophysiological reliance between TMD-related pain and migraine might have a significant impact on the treatment strategies, as well as prognosis, of both conditions.

As with the association of TMD-related pain with TTH, there exists both

epidemiological and physiological evidence. Epidemiological studies, mainly cross- sectional, point toward substantial clinical similarities between TMD-related pain and TTH in the head and face region (Pettengill, 1999; Ciancaglini and Radaelli, 2001). The overlap of the signs and symptoms between TMD-related pain and TTH is particularly evident in mTMD. These common clinical features include

tenderness upon palpation in the masticatory muscles in the case of mTMD and in the pericranial muscles in the case of TTH during the active phases of both

conditions (Svensson, 2007; Bendtsen et al., 2016). The shared clinical features mTMD and TTH may also be due to the close anatomical proximity of the pericranial and masticatory muscles. The literature suggests that muscle tenderness increases throughout the pericranial myofascial region in both the episodic and the chronic types of TTH (Jensen et al., 1998; Buchgreitz et al., 2006).

Repetitive episodes of muscle pain may hypersensitize the central nervous system, leading to the progression to a chronic form of TTH (Bendtsen et al., 2016).

Additional clinical similarities between mTMD and TTH include the individuals’ age regarding the peak prevalence of the disease (Costa et al., 2016), the intensity of the pain, pain during palpation (Bendtsen et al., 2016), pharmacotherapy (Neblett et al., 2013) and even non-pharmacological management (Fernández-De-Las- Peñas and Cuadrado, 2016).

In terms of autonomic system dysfunction, both mTMD (Cairns, 2010) and TTH (Ashina et al., 2005; Bendtsen and Jensen, 2006) share common features, such as a lower PPT and referred pain during the active phases of both diseases (Pinto

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Fiamengui et al., 2013). These features typify the presence of peripheral and central sensitization in their respective nociceptive pathways. A recent study reported a high prevalence of active myofascial TrPs in TTH patients. This finding may support the hypothesis that peripheral muscular mechanisms are involved in the pathophysiology of TTH (Do et al., 2018). Initial evidence also supports the concept of a genetic component involved in the pathogenesis of both mTMD and TTH (Svensson, 2019).

Contrary to mTMD, which is considered a generalized functional disorder, jTMD is considered more of a localized condition (Furquim et al., 2015). Consequently, studies reporting an association between TMD-related pain and primary

headaches have mainly focused on the muscular pain component of the TMD- related pain (Burnett et al., 2000; Hagen et al., 2002; Leistad et al., 2006; Ebinger, 2006; Blaschek et al., 2012; Watson and Drummond, 2012). The localized nature of jTMD renders it less related to primary headaches, for which generalized

mechanisms, such as central sensitization, seem important (Yunus, 2008). This notion is supported by the results of certain studies, which have reported a selective association between mTMD and the presence of primary headaches (Glaros, 2007; Dahan et al., 2016; Goncalves et al., 2011). However, it has been postulated that TMD-related pain originating in the TMJs may affect nociceptive afferents in the trigeminal areas to influence such an effect as headaches, but these afferents may need further activation signals from the muscular part of the temporomandibular area (Gonçalves et al., 2011).

The association between TMD-related pain and cluster headaches has not been studied extensively. However, a case study (Gross, 2006) reported that cluster headaches patients were referred to dental practitioners to rule out the presence of TMD-related pain. Cluster headaches are often confused for trigeminal

neuralgia, maxillary sinus pain or a toothache (Balasubramaniam et al., 2008).

FREQUENTIST VERSUS BAYESIAN STATISTICAL METHODOLOGY

Most studies regarding TMD-related pain and primary headaches, and other areas of medicine in fact, have been traditionally based on Frequentist statistical

methodologies. Frequentist statistics are highly effective tools for randomized trials and randomly sampled surveys for which they were developed. Bayesian statistics, on the other hand, provide better estimations in situations of non- random or nested study samples. In these settings, which typify most in

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epidemiology, subjective criteria of the investigators play a crucial role in making inferences. Likewise, in observational studies, precise computation is not crucially needed, especially considering the uncertainties regarding the processes

generating observational data, as well as uncertainty about prior information (Greenland, 2006).

The Bayesian approach produces a range of values (Bayesian 95% credible intervals [CrIs) as posterior distributions that reflect the uncertainty inherent for the multiple unknown parameters, rather than a fixed value for parameter estimates as in the Frequentist approach. Another advantage of the Bayesian approach is the allowance for the sub-analyses without the need for the classic statistical adjustments for multiple comparisons, such as Bonferroni among others, resulting in less biased and more stable estimation with moderate and smaller sample sizes (Shin and Zurakowski, 2017).

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3 AIMS OF THE STUDY

This thesis aimed to study the associations of two clinically assessed signs of TMD- related pain, mTMD and jTMD, with the presence of primary headaches—namely migraine and TTH— based on the data from Finnish national health surveys, the Health 2000 Survey and the Health 2011 Survey. The current thesis hypothesized that an association exists between TMD-related pain and primary headaches at cross-sectional and longitudinal levels.

More specific aims of this thesis were:

1. To investigate whether TMD-related pain is associated with the presence of migraine cross-sectionally.

2. To investigate whether there is a cross-sectional association of TMD- related pain (mTMD and jTMD) with migraine frequency and the presence of headache medication consumption.

3. To investigate whether TMD-related pain at baseline predicts the presence of migraine or TTH at follow-up.

4. To investigate whether the results of the prospective analyses are consistent across different statistical methodologies, such as the Frequentist and Bayesian approaches.

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4 MATERIALS AND METHODS

STUDY POPULATIONS

4.1.1 The Health 2000 Survey

The Health 2000 Survey (BRIF8901) was a population-based nationally

representative health survey organized in 2000 and 2001 by the Finnish Institute for Health and Welfare (THL) (former National Public Health Institute [KTL] of Finland) in co-operation with the researchers and experts from several other organizations in Finland. The Health 2000 Survey aimed to provide an account of major public health problems in Finland. The Health 2000 Survey also investigated the functional and working capacity of the Finnish population. The data for the Health 2000 Survey were collected by clinical oral and health examinations (participants 30 years or older), laboratory analyses, self-administered

questionnaires, and interviews. Also, the register-based information, such as age, of all the participants of the Health 2000 Survey was linked to the survey data (Aromaa et al., 2004).

The Health 2000 Survey included 9,922 invited individuals aged 18 years or older living in mainland Finland. The response rate amongst these participants was 92% (participation in at least one phase of the survey). Participants aged 30 years or above (n = 8,028 [81.0%) were invited for the clinical health examinations.

From these participants, 79% (n = 6,335) took part in the clinical oral health examination, including the assessment of the temporomandibular area and the grade of malocclusion, comprising 3,466 (55.0%) females and 2,869 (45.3%) males (Aromaa et al., 2004).

The Health 2000 Survey utilized the two-stage stratified cluster sampling design method. The sampling frame was stratified according to five university hospital regions, each containing approximately one million inhabitants. From each region, sixteen health-care districts were selected as clusters. Thus, the 80 health center districts were the primary sampling units (Aromaa et al., 2004).

4.1.2 The Health 2011 Survey

The Health 2011 Survey (BRIF8901) was a follow-up study of the Health 2000

Association between temporomandibular-disorder-related pain and primary headaches : results of finnish population-based surveys

JAVED ASHRAF

Association between temporomandibular- disorder-related pain and primary headaches

—results of Finnish population-based surveys

Dissertations in Health Sciences

ASSOCIATION BETWEEN

TEMPOROMANDIBULAR-DISORDER-RELATED PAIN AND PRIMARY HEADACHES—RESULTS OF

FINNISH POPULATION-BASED SURVEYS

Javed Ashraf

ASSOCIATION BETWEEN

TEMPOROMANDIBULAR-DISORDER-RELATED PAIN AND PRIMARY HEADACHES—RESULTS OF

FINNISH POPULATION-BASED SURVEYS

ABSTRACT

TIIVISTELMÄ

ACKNOWLEDGEMENTS

LIST OF ORIGINAL PUBLICATIONS

CONTENTS

ABBREVIATIONS

1 INTRODUCTION

2 REVIEW OF THE LITERATURE

TEMPOROMANDIBULAR-DISORDER-RELATED PAIN

EVOLUTION OF THE DIAGNOSTIC CRITERIA FOR

TEMPOROMANDIBULAR DISORDERS SIGNS AND SYMPTOMS

ETIOLOGY OF TEMPOROMANDIBULAR-DISORDER-RELATED PAIN

PUBLIC HEALTH SIGNIFICANCE OF TEMPOROMANDIBULAR- DISORDER-RELATED PAIN

PRIMARY HEADACHES

ETIOLOGY AND PATHOPHYSIOLOGY OF PRIMARY HEADACHES

PUBLIC HEALTH SIGNIFICANCE OF PRIMARY HEADACHES

CO-MORBIDITIES ASSOCIATED WITH

TEMPOROMANDIBULAR-DISORDER-RELATED PAIN

ASSOCIATION BETWEEN TEMPOROMANDIBULAR-DISORDER- RELATED PAIN AND PRIMARY HEADACHES

FREQUENTIST VERSUS BAYESIAN STATISTICAL METHODOLOGY

3 AIMS OF THE STUDY

4 MATERIALS AND METHODS

STUDY POPULATIONS