Orofacial Pain & Headache Second Edition

Orofacial Pain and Headache Second Edition

Edited by

Yair Sharav, dmd, ms Professor Department of Oral Medicine School of Dental Medicine Hadassah Medical Center The Hebrew University of Jerusalem Jerusalem, Israel

Rafael Benoliel, bds Associate Dean for Research Professor, Department of Diagnostic Sciences Director, Center for Orofacial Pain and Temporomandibular Disorders Rutgers School of Dental Medicine Rutgers, The State University of New Jersey Newark, New Jersey

Quintessence Publishing Co, Inc

Chicago, Berlin, Tokyo, London, Paris, Milan, Barcelona, Istanbul, Moscow, New Delhi, Prague, São Paulo, Seoul, and Warsaw Library of Congress Cataloging-in-Publication Data

Orofacial pain and headache / edited by Yair Sharav and Rafael Benoliel. -- Second edition. p. ; cm. Includes bibliographical references and index. ISBN 978-0-86715-680-5 (softcover) I. Sharav, Yair, editor. II. Benoliel, Rafael, editor. [DNLM: 1. Facial Pain. 2. Headache Disorders. WE 705] RC936 616’.0472--dc23 2015003559

© 2015 Quintessence Publishing Co, Inc

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Printed in the USA Contents

Preface to the Second Edition vii Preface to the First Edition viii Contributors ix

The Diagnostic Process 1 1 Yair Sharav and Rafael Benoliel

Anatomy and Neurophysiology of Orofacial Pain 31 2 Michael Tal, Luis Villanueva, and Marshall Devor

Measuring and Assessing Pain 79 3 Eli Eliav and Richard H. Gracely

Psychologic Aspects of Chronic Orofacial Pain 97 4 Karen Raphael and Donald S. Ciccone

Orofacial Pain, Headache, and Sleep 123 5 Rachel E. Salas, Charlene E. Gamaldo, Bonnie Kaas, B. Lee Peterlin, and Michael T. Smith

Acute Orofacial Pain 141 6 Yair Sharav and Rafael Benoliel

Otolaryngologic Aspects of Orofacial Pain 163 7 Menachem Gross and Ron Eliashar

Myalgia, Myofascial Pain, Tension-Type Headaches, and Fibromyalgia 195 8 Peter Svensson, Yair Sharav, and Rafael Benoliel Pain and Dysfunction of the Temporomandibular Joint 257 9 Dorrit W. Nitzan, Gary M. Heir, M. Franklin Dolwick, and Rafael Benoliel

Migraine and Possible Facial Variants: Neurovascular Orofacial Pain 319 10 Yair Sharav, Zaza Katsarava, and Rafael Benoliel

The Trigeminal Autonomic Cephalalgias 363 11 Rafael Benoliel and Yair Sharav

Neuropathic Orofacial Pain 407 12 Rafael Benoliel, Gary M. Heir, and Eli Eliav

Neurosurgical Aspects of Orofacial Pain 475 13 Zvi Harry Rappaport

Secondary Orofacial Pain and Headache: Systemic Diseases, Tumors, and Trauma 487 14 Sharon Elad, Herve Sroussi, Gary D. Klasser, and Joel Epstein

Pharmacotherapy for Acute Orofacial Pain 541 15 Yair Sharav and Rafael Benoliel

Pharmacotherapy for Chronic Orofacial Pain 583 16 Rafael Benoliel and Yair Sharav

Complementary and Alternative Medicine 623 17 Yair Sharav and Rafael Benoliel Index 639 Preface to the Second Edition

hen we published the fi rst edition of this book, we felt there was a true need to bridge the fi elds of orofacial pain and headache with a textbook that could integrate the knowledge W from both fi elds. While at the time we questioned the necessity for an additional book in the area of craniofacial pain, this worry soon became unnecessary. The book was accepted with great enthusiasm, and in 2009, the British Medical Association highly commended the fi rst edition as one of the best books published in the medical fi eld. Reviews were complimentary: “This text- book is a joy to read,” proclaimed a 2008 review in the Journal of Orofacial Pain (Quintessence Publishing). The reviewers praised our success in integrating the broad topics of orofacial pain and headache. Furthermore, we were glad to see that this most important journal in the orofacial fi eld changed its name in 2014 from the Journal of Orofacial Pain to the Journal of Oral & Facial Pain & Headache, pointing to what was already obvious to us; these two fi elds must continue to be integrated. Integration ensures that we are consistent and relate all regional craniofacial pains to each oth- er, thereby presenting the wider picture of craniofacial pain syndromes and the overlap between primary headaches and primary orofacial pain entities. Truly, the years since the fi rst edition was published have seen some integration of the two fi elds, particularly through close collaboration be- tween dental and medical professionals for the preparation of the 2013 International Classifi cation of Headache Disorders. In spite of this, the International Headache Society’s classifi cation system does not yet adequately cover all currently accepted orofacial pain entities. Therefore, we added the recently reviewed classifi cation of the Diagnostic Criteria for Temporomandibular Disorders (DC- TMD) and drew from our wide experience in the fi eld. Certainly, in the diagnosis of acute dental and otolaryngological pain, we have continued to stress the importance of accurate, evidence-based diagnosis. This may seem oversimplistic at fi rst, but consider the reports of misdiagnosis of cluster headache, paroxysmal hemicrania, migraine, and trigeminal neuralgia as dental pains or sinus head- aches. The results to our patients are often devastating and unnecessary. Clearly as a profession, we still have hurdles to overcome. While we preserved the well-structured format of the last edition, we updated the chapters to refl ect current knowledge and added a new chapter on orofacial pain and sleep, as data continues to point to their interconnection. We have also made this edition friendlier to clinicians. In many chapters, we fi rst address the clinical picture and treatment strategies and follow with a discussion of the underlying mechanisms. In addition, the design has been updated, and we have found that the esthetic layout of the present edition, made possible by the excellent editors and production staff of the Quintessence Publishing house, makes the excursion through the pages of this book a most pleasant experience. Finally, as the fi rst edition was highly praised, we felt that we were not in a position to disappoint our faithful readers and had to keep to the high standards that are expected. We very much hope we have succeeded in this mission.

vii Preface to the First Edition

or many years, the area of orofacial pain was completely dominated by the concept that most facial pains were due to “disturbed function” of the temporomandibular joint (TMJ). F This was an approach established by an otolaryngologist named James B. Costen who linked etiology to derangements of the dental occlusion; facial pain was thus handed over to den- tistry. As a profession, we enthusiastically adopted the treatment of facial pain but have for many years concentrated our efforts on a mechanistic approach to treatment. These events essentially segregated facial pain from headache and, in effect, from mainstream medicine. As a result, ideal conditions were established in each of the two disciplines for the development of different ap- proaches to the understanding of mechanisms and therapy of craniofacial pain. However, as our understanding of pain mechanisms, and in particular chronic pain, developed, it became clear that facial pain has underlying neurophysiologic mechanisms common to headaches and other body areas. Masticatory muscle pain was examined in light of other regional muscle pains, and management of the TMJ was related to, and brought in line with, basic orthopedic principles. Most importantly, features of some facial pain entities are very similar to those of some head- aches. Examples include masticatory myofascial pain and tension-type headache and a facial equivalent of migraine. The dental profession has been slow in adopting medically based classification and approaches to therapy. In a similar fashion, the medical profession has been very resistant to incorporating es- tablished facial pains into current classifications; temporomandibular disorders are a prime example and currently unrecognized by the International Headache Society. One may correctly claim that toothache is unique, but is it really? On a mechanistic level, pulpitis is an inflammatory process within a confined space—not very different from the inflammatory pro- cess of migraine confined within the skull. Indeed, we believe that migraine-like mechanisms exist within the pulp chamber mimicking pulpitis, in the paranasal sinuses imitating sinusitis, and in other confined cranial structures causing atypical symptomatology. In each of these cases, anti-migraine medications are the correct treatment. Clearly the task required is integration of knowledge in this anatomically dense region, tradi- tionally divided between many medical disciplines. Based on our extensive clinical experience with patients suffering from orofacial pain and headache as well as our thorough understanding of pain mechanisms specific to the trigeminal system, we feel that we are well equipped to fulfill this task. This textbook therefore deals with oral and facial pain as well as with headaches and aims to inte- grate the knowledge across these disciplines. We hope we have succeeded. We appreciate the contribution of our teachers, colleagues, and students. Throughout our pro- fessional lives, we have interacted with many professionals worldwide, and each has enriched our understanding of pain mechanisms and our clinical knowledge. Being in the “business” of teaching, both undergraduates and residents, we have been consistently challenged by curious students with difficult questions. These have kept us up to date and enabled us to re-examine and reassess the way orofacial pain is understood and taught. Last but not least, our warm gratitude and appreciation to our families for bearing with us through the long process of preparing, writing, editing, and publishing this book.

viii Contributors

Rafael Benoliel, bds Eli Eliav, dmd, msc, phd Associate Dean for Research Professor and Director Professor, Department of Diagnostic Sciences Department of Dentistry Director, Center for Orofacial Pain and Temporomandibular Eastman Institute for Oral Health Disorders University of Rochester Medical Center Rutgers School of Dental Medicine Rochester, New York Rutgers, The State University of New Jersey Newark, New Jersey Joel Epstein, dmd, msd, frcd(c), fds rcs(edin) Consulting Staff Donald S. Ciccone, phd Division of Otolaryngology and Head and Neck Surgery Adjunct Associate Professor City of Hope National Medical Center Department of Psychiatry Duarte, California New Jersey Medical School Rutgers, The State University of New Jersey Charlene E. Gamaldo, md Newark, New Jersey Medical Director Johns Hopkins Sleep Disorders Center Marshall Devor, phd The Johns Hopkins Hospital Professor and Chairman Baltimore, Maryland Department for Cell and Animal Biology Institute of Life Sciences Richard H. Gracely, ms, phd The Hebrew University of Jerusalem Professor Jerusalem, Israel Division of Rheumatology Department of Internal Medicine M. Franklin Dolwick, dmd, phd University of Michigan Professor and Division Head Ann Arbor, Michigan Department of Oral and Maxillofacial Surgery University of Florida College of Dentistry Menachem Gross, md Gainesville, Florida Department of Otolaryngology, Head and Neck Surgery Hadassah Medical Center Sharon Elad, dmd, msc The Hebrew University of Jerusalem Professor Jerusalem, Israel Department of Dentistry Eastman Institute for Oral Health Gary M. Heir, dmd University of Rochester Medical Center Clinical Professor Rochester, New York Department of Diagnostic Sciences Rutgers School of Dental Medicine Ron Eliashar, md Rutgers, The State University of New Jersey Professor and Director Newark, New Jersey Department of Otolaryngology, Head and Neck Surgery Hadassah Medical Center Bonnie Kaas, md The Hebrew University of Jerusalem Assistant Resident Jerusalem, Israel Department of Neurology The Johns Hopkins Hospital Baltimore, Maryland

ix Zaza Katsarava, md, phd, msc Yair Sharav, dmd, ms Chair Professor Department of Neurology Department of Oral Medicine University of Essen School of Dental Medicine Essen, Germany Hadassah Medical Center The Hebrew University of Jerusalem Gary D. Klasser, dmd Jerusalem, Israel Associate Professor Department of Diagnostic Sciences Michael T. Smith, phd School of Dentistry Professor of Psychiatry, Neurology, and Nursing Louisiana State University Health Sciences Center Director, Center for Behavior and Health New Orleans, Louisiana Co-Director, Center for Sleep-Related Symptom Science Johns Hopkins University School of Medicine Dorrit W. Nitzan, dmd Baltimore, Maryland Professor and Senior Surgeon Department of Oral and Maxillofacial Surgery Herve Sroussi, dmd, phd Hadassah Medical Center Associate Professor and Chief of Oral Medicine The Hebrew University of Jerusalem Director of Graduate Studies Jerusalem, Israel Department of Oral Medicine and Diagnostic Science University of Illinois at Chicago College of Dentistry B. Lee Peterlin, do Chicago, Illinois Associate Professor of Neurology Director, Headache Research Peter Svensson, dds, phd, dr odont Johns Hopkins University School of Medicine Professor Baltimore, Maryland Division of Orofacial Pain and Jaw Function Department of Dentistry Karen Raphael, phd Aarhus University Professor Aarhus, Denmark Department of Oral and Maxillofacial Pathology, Radiology and Medicine Michael Tal, dmd, ms New York University College of Dentistry Professor New York, New York Department of Anatomy and Cell Biology School of Medicine Zvi Harry Rappaport, md The Hebrew University of Jerusalem Director, Department of Neurosurgery Jerusalem, Israel Rabin Medical Center Petah Tikva, Israel Luis Villanueva, dds, phd Director of Research Rachel E. Salas, md Department of Dentistry Assistant Professor Psychiatry and Neurosciences Center Department of Neurology French Institute of Health and Medical Research Johns Hopkins University School of Medicine Paris, France Baltimore, Maryland

x The Diagnostic Process 1 Yair Sharav, DMD, MS Rafael Benoliel, BDS

Diagnosis and treatment of orofacial pain is a complex process compounded by the density of anatomical structures and the prominent psychologic signifi cance attributed to this region. Man- agement of orofacial pain thus demands the services of clinicians from various specialties, such as dentistry, otolaryngology, ophthalmology, neurology, neurosurgery, psychiatry, and psychology. Complex referral patterns to adjacent structures are common in orofacial pain and, indeed, one person’s headache is another person’s facial pain. In clinical practice, the two types of pain are often intimately related. Consequently, a patient with orofacial pain may wander from one specialist to another to try to fi nd adequate help. The second edition of this textbook continues to integrate the issue of orofacial pain with head- ache through contributions from practitioners in different disciplines, all of whom have extensive clinical experience and a thorough understanding of pain mechanisms specifi c to the trigeminal system. Accordingly, the authors address all regional craniofacial pains together and aim to present a wider picture of orofacial pain syndromes, including the overlap between primary headaches and primary orofacial pain entities. Many patients with chronic orofacial pain suffer primary headache variants in the orofacial region, and a lack of familiarity with these syndromes is likely a factor in misdiagnosis by dental practitioners and medical specialists. Other patients may suffer from prima- ry orofacial pain entities that remain unclassifi ed by the International Headache Society (IHS) and are unknown to neurologists, otolaryngologists, other medical practitioners, and even dentists.1–3 The integration of headache and orofacial pain classifi cations is of paramount importance. In the past, about half of the patients in tertiary-care craniofacial pain clinics were labeled as “idiopathic” or “undiagnosable” when the previous IHS classifi cation was applied.2–5 The hope is that the current classifi cation, which has witnessed a novel collaboration between orofacial pain and headache specialists, will improve the situation. Moreover, there is considerable overlap in the clinical presentation of headaches, such as ten- sion type with regional myofascial pains of the face, and generalized pain syndromes, such as

1 1 The Diagnostic Process

fibromyalgia (see chapter 8). The relationship Both acute and chronic presentations may be between isolated facial neurovascular pain (see benign or may signify serious underlying dis- chapter 10) and migraines or trigeminal auto- ease. The emphasis of this book is on the four nomic cephalalgias remains unclear and is not major clinical families of orofacial pain: acute accounted for by the recent IHS classification.6 orofacial, neurovascular, musculoskeletal, and Furthermore, a growing patient population has neuropathic (see chapters 6 and 8 to 12). In chronic craniofacial pain from trauma associat- these chapters, the current etiology, diagnosis, ed with traffic accidents or from invasive dental and treatment are reviewed. The book includes procedures, such as dental implants, which de- many case presentations that are largely virtual, mands a multidisciplinary approach. This book that is, created by integrating data from a num- bridges the gap between medically trained ber of cases seen in the clinic; thus, any resem- headache and dentally trained orofacial pain blance to specific cases is purely coincidental. specialists. It will be useful to readers at differ- They are real, however, in that they reliably du- ent stages of their careers—undergraduate stu- plicate the type of cases seen in orofacial pain dents, residents, practitioners, and dental and clinics. Typical textbook cases are rare, and medical pain specialists. each relevant section includes information re- lated to the changes in presentation that may cause diagnostic confusion. Atypical cases may be difficult to manage; many have super- Epidemiology: imposed trauma and consequent neuropathic The Silent Crisis pain. Some of these cases present patients with a history of misdiagnosed acute pains in the Statistics from the United States indicate that orofacial region who have undergone repeated 100 million adults suffer from chronic pain7 at and unsuccessful interventions that slowly es- an estimated annual cost of around $600 bil- calated and resulted in dental extractions and lion—higher than the cost for heart disease, surgeries. Accurate diagnosis of acute dental cancer, or diabetes. However, chronic pain is and orofacial conditions is therefore essential a worldwide epidemic that has been termed (see chapter 6). The importance of acute and “the silent crisis.”8 Examining relevant preva- chronic otolaryngologic syndromes in the dif- lence estimates gives important insight into the ferential diagnosis of facial pain, particularly scope of the problem. Orofacial pain, of which migraines and cluster headache, is paramount about 10% is chronic, affects around a quarter (see chapter 7). The growing number of older, of the general population.9–11 Painful temporo- often medically compromised, patients with mandibular disorders (TMDs) are quite preva- orofacial pain deserves special attention (see lent; 4.6% of the population reports this type chapter 14): Is orofacial pain in these patients of pain (6.3% of women, 2.8% of men).12 This related to their medical condition? Although finding is in agreement with the 2009 National this is essentially a clinical book, anatomy and Health Interview Survey, which found that 5% neurophysiology are covered in a manner spe- of adults reported pain in the face or jaw over cifically relevant to the topic of orofacial pain a 3-month period. Persistent facial pain, which (see chapter 2). has a reported incidence of 38.7 per 100,000 One of the mainstays of pain management person-years, is more common in women and is indisputably pharmacotherapy. Because increases with age.13 Syndromes identified in- many drugs are commonly used to treat many cluded trigeminal neuralgia and cluster head- syndromes, two separate chapters on phar- ache, which are the most common forms. macotherapy are included: acute and chronic Paroxysmal hemicrania and glossopharyngeal (see chapters 15 and 16). The management of neuralgia were among the rare syndromes. pain relies on accurate diagnosis and reliable Clearly, orofacial pain is more prevalent than follow-up that demonstrates objective improve- previously thought. ment. Chapter 3 covers the important area of Therefore, diagnosis and management of pain measurement as well as the assessment of orofacial pain and headache have become pain modulatory systems and peripheral nerve important subjects in medicine and dentistry. function. Unfortunately, we are a long way from

2 Chronic Pain Is a Disease optimal patient care, and some of the best drugs damaged, the local inflammatory response offer notable relief for only a fraction of our pa- causes increased sensitivity in peripheral no- tients, with some having disturbing side effects. ciceptors (peripheral sensitization) and dorsal Many patients inquire about complementary and horn neurons (central sensitization) associated alternative medicine and often actively search with pain transmission. As a result, the hand is out these practitioners independently (see sensitive to touch and more sensitive to pain chapter 17). Neurosurgical approaches, includ- (allodynia and hyperalgesia; see Table 1-1) so ing neuromodulation, remain relevant options for that the person protects and immobilizes the selected syndromes (see chapters 11 to 13). No limb to aid rapid healing. Essentially, the system diagnosis and treatment of orofacial pain would has been altered to behave differently. In most be complete without understanding its emotion- cases, tissue injury is followed by a healing pe- al undercurrents and having a thorough knowl- riod associated with ongoing pain that ultimate- edge of its psychologic aspects and treatment ly resolves with no residual problems. possibilities, which are covered in chapter 4. A In contrast, pain with no biologic advantage novel and welcome addition to this second edi- to the person is termed “bad” pain. For example, tion is a description of the interactions between chronic pain that is not associated with ongoing sleep and orofacial pain and headaches. tissue damage, but inflicts severe physical and emotional suffering on the person, offers no sur- vival value. Chronic pain is often the result of pri- Chronic Pain Is a Disease mary or reactive changes in the nervous system that are associated with neuronal plasticity but Pain is a multifaceted experience with physical, are unable to modulate and thus actually serve cognitive, and emotional aspects (Table 1-1). to perpetuate the sensation of pain; in short, the Three mechanistically distinct types of pain are system has malfunctioned, and maladaptive distinguishable: nociceptive, inflammatory, and pain remains. Chronic pain is, therefore, a dis- neuropathic. Nociceptive pain is the baseline ease in its own right and often not a symptom. defensive mechanism that protects us from Additionally, chronic pain responds to therapy potential harm. Inflammatory and neuropathic differently from acute pain and is associated pains are characterized by altered and often with emotional and social behavioral changes aberrant function of the nervous system as a (see chapter 4). Acute and chronic pains differ in result of persistent pathology or plastic chang- many respects, and some of the major differenc- es in the nervous system. es are presented in Table 1-2. Thus, although we tend to call any sensa- Patients, and sometimes physicians, find it tion that hurts “pain,” many types of pain exist hard to distinguish pain as a disease from pain that subserve various biologic functions. For as a symptom. The latter signifies an expres- example, acute pain from extreme heat initiates sion of a pathologic process that, if treated, will a reflex withdrawal and ensures minimal tissue cause the pain to disappear. Unfortunately, the damage (nociceptive pain). This type of pain inability to perceive pain as a disease may re- is a survival mechanism and may be termed sult in repeated and unsuccessful interventions, “good” pain. Consequently, if tissue has been all in an attempt to eradicate the cause of pain.

3 1 The Diagnostic Process

Table 1-1 Definition of pain terms Term Definition Clinical implication Pain An unpleasant sensory and emotional Some patients may be unable to experience associated with actual or communicate verbally. Pain is an potential tissue damage, or described in individually subjective experience. terms of such damage. Allodynia Pain due to a stimulus that does not Associated with neuropathy, inflammation, normally provoke pain (eg, touch, light and certain headache states (see chapters pressure, or moderate cold or warmth). 5, 9, and 11). A lowered threshold where the stimulus and response mode differ from the normal state. Hyperalgesia An increased response to a stimulus that is Associated with neuropathy or normally painful. inflammation. Reflects increased pain on suprathreshold stimulation. The stimulus and response mode are basically the same. Hyperesthesia Increased sensitivity to stimulation, excluding Associated with neuropathy or the special senses. Includes both allodynia inflammation (see chapter 11). and hyperalgesia. Hypoalgesia Diminished pain in response to a normally Typical of neural damage. Raised painful stimulus. threshold: stimulus and response mode are the same (lowered response). Analgesia Absence of pain in response to stimulation Commonly observed after complete that would normally be painful. axotomy or nerve block. Not unpleasant. Hyperpathia A painful syndrome characterized by an Typical of neuropathic pain syndromes abnormally painful reaction to a stimulus, (see chapter 11). Faulty identification especially a repetitive stimulus, as well as and localization of the stimulus, delay, an increased threshold. May occur with radiating sensation, and after-sensation allodynia, hyperesthesia, hyperalgesia, or may be present, and the pain is often dysesthesia. explosive in character. Paresthesia An abnormal sensation, whether Typical of neuropathic pain syndromes spontaneous or evoked. (see chapter 11). Hypoesthesia Decreased sensitivity to stimulation, excluding the special senses. Dysesthesia An unpleasant abnormal sensation, whether spontaneous or evoked. Hyperalgesia and allodynia are forms of dysesthesia.

4 Classification, Disease, and Diagnosis

Table 1-2 Major features of acute and chronic pain Features Acute pain Chronic pain Time course Short (hours to days) Long (months to years) Etiology Peripheral (inflammatory) Central (neuropathic) Behavioral Anxiety, “guarding” Depression, “illness behavior” response Response to treatment Local intervention Good Poor Analgesic drugs Good Poor Psychotropic drugs Poor Moderate to good

Approach to Diagnosis Classification, Disease, and Management and Diagnosis The need to base therapeutic approaches on In the clinical setting as much as in the research evidence-based medicine is obvious, and the setting, classification systems are important. authors wholeheartedly agree with this ap- Diagnoses (based on classifications) usual- proach. Thus, this book cites state-of-the-art ly dictate therapeutic options and indicate a research to support statements whenever pos- prognosis. A number of relevant classifications sible. However, evidence-based medicine is a are available for orofacial pain and headache, tasteless science unless peppered by clinical though they are not in complete accord.14 The experience and judgment, careful appraisal of IHS,6 the American Academy of Orofacial Pain drug side effects and complications (especially (AAOP),15 and the Research Diagnostic Criteria in the medically compromised patient), the in- for Temporomandibular Disorders (RDC-TMD)16 dividual variability of patients, and a respectful have all recently reviewed their classifications. approach to a patient’s autonomy. Therefore, These classifications often have offshoots expert opinion also enriches this text. based on specific characteristics. Thus, chronic As in most other textbooks of medicine, this facial pain17 or chronic daily headache18 may be book presents knowledge in a linear, disease- subclassified as temporal, and indomethacin- based manner. Pain syndromes are described responsive headaches19 may be subclassified and their signs, symptoms, and associated as therapeutic. The former is probably most features outlined. This is very different from the useful in epidemiologic and disease-burden circular process of clinical data collection; in- studies, whereas the latter presents a deed, patients present with complaints rather treatment-dependent diagnostic challenge. than diseases. Knowledge of a disease does However, both classification approaches offer not automatically guarantee the ability to iden- little advantage in guiding clinical diagnosis and tify it from a given set of signs and symptoms. therapy.17 The process of accumulating clinical data in The concept that diseases are identifiable order to reach a diagnosis is as much a sci- through their symptomatology is the basis of ence as it is an art, and part of this chapter classifications.20 Classifications aim to organize is devoted to understanding and applying this orofacial pains, some headaches, and TMDs process. into a logical and applicable system. The lev-

5 1 The Diagnostic Process

el of detail of the classification depends on its cussed in the clinical chapters. For example, a planned use or requirements. Over the years, tension-type headache (TTH) may be extreme- research has enriched medical practice with ly difficult to differentiate from a mild migraine specific diagnostic biomarkers, but these are without aura because of overlap in the appear- largely unavailable in the field of orofacial pain ance of ostensibly diagnostic features. Mild and headache. In the absence of adequate bio- nausea and photo- and phonophobia may form markers, the diagnosis of orofacial pain and part of the TTH phenotype,6 TTH may be ag- headache is based on a clinician’s ability to gravated by exercise,29 regional muscle tender- recognize a particular combination of signs and ness is equally prevalent in both,30–32 and even symptoms in a patient. Thus, diagnosis remains headache precipitants are identical between heavily reliant on the patient’s story—the way migraine and TTH.33 it is related and how the clinician interprets it. Problems occur even with specifically tai- Of course, diagnosis should not be con- lored classifications; recent reliability studies on fused with disease, as in all areas of medicine the RDC-TMD conclude that the specified clin- diagnoses are often made for unknown under- ical tests identified as independent diagnostic lying processes. Consider migraine, which was criteria would be unacceptably susceptible to once thought to be a vascular headache. After diagnostic misclassification. The more com- further scientific investigations, we now appre- mon diagnoses had good examiner reliability, ciate the complexity of the underlying central but some lack of agreement was clearly pres­ ­ nervous system events leading to a migraine ent, even when well-trained examiners perform and the vascular changes understood as epi- these procedures.34 phenomena.21 As we elucidate exact processes Field-testing of classifications often reveal underlying a disorder, diagnosis approaches novel subtypes of the same diagnosis or new etiology and, ultimately, the true disease.22 diagnoses hidden within previous ones. Thus, Clearly, in orofacial pain and headache the cluster headache was extracted from migraines, aim of diagnosing all entities is unattainable. and paroxysmal hemicrania was subsequently Therefore, classifications commonly have one subclassified from cluster headache. In the field or more “other” diagnoses or categories. In- of TMDs, the recognition and classification of deed, we all have patients with chronic orofa- separate joint and muscle disorders in the late cial pain whose diagnosis remains elusive3,23–25 1980s and early 1990s35,36 opened an oppor- and whose signs and symptoms cannot be tunity to revise old and irrelevant terminology. neatly pigeonholed into established diagnoses. Much of this work has been admirably complet- Many of these entities share temporal features, ed in regard to joint disorders but is still lacking such as pain for most or all of the day that is in regard to muscle pain, particularly chronic long-standing or chronic (> 3 months). Past at- masticatory muscle pain, which is often termed tempts at terminology have left us with diag- myofascial masticatory muscle pain, a term noses of such diseases as atypical odontalgia, based on an outdated premise that the muscle atypical facial pain, and persistent idiopathic and surrounding fascia are the origins of pain. facial pain; these classifications are inade- Multi-axis systems recognize the bio- quate. More recently, Nixdorf et al26 exercised psychosocial model of pain, which reflects the the classification of such cases based on on- inherent complexity of the pain experience and tologic principles and suggested the term per- the clear relationship between onset, treatment sistent dentoalveolar pain disorder. These gen- response, and psychosocial issues.37–39 For ex- eral terms may be accurate in the symptomatic ample, the RDC-TMD includes a separate axis description but may also tend to lump together for the classification of psychosocial dysfunc- a number of underlying diagnostic entities that tion/suffering. It would clearly be an advantage may present with similar, but subtly different, to have an integrated classification of orofacial clinical phenotypes; thus, their contribution to pain and headache that takes into account psy- management may be minimal.27,28 chosocial comorbidity. The assessment of psy- Existing classifications are not always ac- chologic distress may be performed with the curate or adequate. Often syndromes overlap RDC-TMD questionnaire or with established in their clinical phenotype, and these are dis- alternatives.40,41

6 Diagnosis of Orofacial Pain

As health care providers, we have become tions—where, what, and why—and if possi- increasingly dependent on a wide array of lab- ble, ask them in this order. The first, where, oratory and imaging studies to diagnose and is concerned with the location, such as the subsequently manage patients’ diseases.42 We anatomical structure or system affected. The must, however, appreciate the limitation of di- second, what, deals primarily with the patho- agnostic tests in any clinical setting but particu- logic process. The third, why, is about the eti- larly in the diagnosis of orofacial pain and head- ology. The patient’s decision to seek medical ache. Not only are diagnostic tests inherently help is the first step in the diagnostic chain; limited as diagnostic tools, but there are also surprisingly, not all patients with significant few biomarkers in current use for the diagnosis pain seek treatment. Based mostly on the of primary orofacial pain43–45 and headache46–49 pain location, patients will choose which spe- disorders. In the absence of biomarkers, clas- cialist to consult. Naturally, if it is a toothache, sifications are self-defining and difficult to vali- the patient decides to consult the dentist, and date. However, as biotechnology improves, we most times the choice will be correct. How- may be able to incorporate specific biomarkers ever, suppose the patient’s pain is referred into classification criteria, whether as a sepa- to the oral cavity from a remote organ (such rate axis or integrated. Biomarkers will aid in as the heart; see chapter 14) or is associated diagnosis and enable assessment of disease with migraine-like mechanisms (see chapter control or severity, much as levels of fasting glu- 10), and he or she consults a dentist. The pa- cose levels and glycated hemoglobin are used tient has clearly, and understandably, missed for diabetes. Ongoing research may change the or misinterpreted the “where” or the “what.” situation, but currently the predictive value of The clinician’s responsibility is to analyze the available biomarkers in primary orofacial pain/ patient’s complaints and reach the correct headache diagnosis is very low. diagnosis. In other words, the clinician has All of these classification systems are inte- to rigorously apply the diagnostic process grated in this book according to their strengths to accurately define the location, identify the in the following manner. The authors have no pathologic process, and ideally establish the doubt that for headaches the IHS is the most etiology of the pain. comprehensive, so it is used throughout this The natural starting point is a comprehen- book for all headache entities. For orofacial pain sive gathering of information. Clinicians rou- entities, the IHS classification is not detailed tinely start with history taking, the strongest enough; thus, the AAOP’s criteria is used, and tool when it comes to the diagnosis of pain. specifically for TMDs, the Diagnostic Criteria Pain symptoms should specify location, dura- for TMD (DC/TMD) is used. The strength of the tion, pain characteristics, and other pertinent International Association for the Study of Pain data (see the section titled “The Pain History”). (IASP) lies in its regional and systems approach In addition, a thorough personal history should to pain classification (eg, musculoskeletal, neu- include details on medical, drug, and psycho- rovascular pain) and to the excellent approach social history; occupation; stress; family history to neuropathic pain entities. The integration of relating to marital status and recent events (eg, such internationally accepted systems into pain bereavement); and any history of familial dis- clinics and research studies is essential and ul- orders (eg, migraine, diabetes). The physical timately an enriching endeavor. examination is next, supplemented by other tests as needed. Once this process has been completed, a working hypothesis needs to be generated, namely, a diagnosis. Gathering in- Diagnosis of formation is a starting point but does not on Orofacial Pain its own make a diagnosis. In the sections that follow, the process of using the patient’s clini- Faced with a patient with a pain complaint, cal data to generate diagnostic hypotheses is clinicians have to answer three major ques- described.

7 1 The Diagnostic Process

Fig 1-1 Suggested diagram for indicating pain location.

interview and examination findings is useful Getting to Know (Fig 1-1 and Forms 1-1 and 1-2), particularly for teaching and training. The intake systematically Your Patient and records the basic information needed in a pain the Patient’s Pain history (Box 1-1), and practitioners can design their own forms based on these principles. Addi- Patients are normally willing to tell their story or tionally, the structured intake, or form, presents pain history, but the clinician usually needs to questions and examination procedures vital to supplement this information with specific ques- the diagnosis of the more common clinical con- tions concerning the location, temporal behav- ditions (see chapters 8 to 12); for this, accepted ior, intensity, relation to function, and sensory classification systems such as those from the modalities. A structured intake for the clinical IHS, the AAOP, and the IASP are relied upon.

8 Getting to Know Your Patient and the Patient’s Pain

1. Patient’s details Name ______Age ____ Sex (M/F) Marital status ______Occupation ______

2. Medical status Summary of relevant medical conditions, medications, etc (patient must com- plete a detailed medical questionnaire, not shown here) ______

3. Pain complaint • Pain location (also marked on pre-prepared drawing, see Fig 1-1)______

• Pain onset and duration ______• Age at onset of pain attacks ______• Pain attack frequency (mark continuous if no pain-free periods) ______

• Pain attack duration ______• Pain severity (mark on scale below (10-cm line)

No pain Worst pain

Factors that precipitate/aggravate pain ______Pain is eased by ______Pain quality (pressing/piercing/throbbing/burning/electric/sharp/other) ______

4. Accompanying signs and symptoms • Systemic: nausea/vomiting/photophobia/phonophobia/dizziness • Local: tearing/rhinorrhea/swelling/redness

5. History of trauma (Yes/No) If yes: date ______Description ______

6. Pain history summary (additional details including response to previous treatments) ______

7. Pain in other body regions (also mark on Fig 1-1) ______

8. How does your pain affect your quality of life?

No effect Extremely

9. How well do you sleep?

Very well Extremely badly

10. Does the pain wake you? (Yes/No) Frequency: times / night

Comments: ______

Form 1-1 Pain history.

9 1 The Diagnostic Process

1. Extraoral examination • Head and neck (mark any asymmetry, change in color, swellings, etc) ______

• Lymph nodes ______

2. TMJ and masticatory muscles examination (mark tenderness to palpation on a scale from 0 to 3: 0 = no tenderness, 3 = very tender)

Muscles Right Left TMJ Right Left Opening (mm) Masseter Lateral tenderness Maximum open Temporalis External auditory Deviation meatus tenderness (right, left) Medial pterygoid Right occlusal Lateral loading movement (right) Lateral pterygoid Left occlusal loading Lateral movement (left) Suboccipital Click* Sternocleidomastoid Reciprocal click* Trapezius Crepitation

*Mark presence and the interincisal opening at which click occurs.

3. Cranial nerves (mark if examined and intact; findings to be summarized under “Remarks”) • Corneal reflex ____ • Pupillary reflex ____ • III, IV, VI eye movements ____ • Vth sensory ____ • Vth motor ____ • Facial (VII) ____ • IX ____ • XI ____ • XII ____ • Remarks:______

4. Intraoral examination (summary) ______

5. Ancillary tests, radiographs (modality and summary of findings)______

6. Discussion of findings and suggested diagnosis______

7. Treatment plan  (medications, other treatment modalities, follow-up planning) ______

Form 1-2 Physical examination. TMJ, temporomandibular joint.

10 The Pain History

Box 1-1 Essentials of an orofacial pain history

• Location • Associated features or signs: local, systemic – Local: head, neck, intraoral • Aggravating factors – Other body regions – Local: thermal, function • Attack onset – Systemic: dialysis, stress – Time of day: morning, midday, evening • Alleviating factors – Month (menstrual) – Endogenous: sleep – Year (seasonal) – Exogenous: analgesics, massage • Attack duration: seconds, minutes, hours, days • Impact on daily function: lost work days, marital • Attack frequency relations, wakes patient from sleep – 24-hour distribution • Personal and social history: occupation, stress, – Use of pain diaries function; psychosocial evaluation • Onset of present problem: age at onset, • Family history: headache, facial pain, associated events, trauma bereavement • Severity: verbal or visual analog scales • Medical status: eg, hypertension • Quality • Drug history: eg, analgesic drug abuse – Verbal descriptions: stabbing, burning – Structured questionnaires: McGill

borders and is usually outlined by patients with The Pain History the whole hand rather than by finger pointing. Pain may radiate, which means the pain felt in a Location certain point spreads in a vectorlike fashion, or Precisely identifying location is a complex issue may spread in all directions. Pain radiation and when specifically dealing with orofacial or cra- pain spread are usually associated with severe niofacial pain; the region is compact, and many pain (see chapter 6). When the source of pain is important structures are close together (brain, in one location but felt in another remote loca- eyes, nose, sinuses, and teeth), so pain spread tion, the pain is called referred. In many cases, is common. Notwithstanding, certain cranio- the patient is usually aware only of the pain in facial pain syndromes have a propensity for the area of referral, and the primary source or particular areas and specific referral patterns. location is identified by the clinician at a later In order to record location, patients should stage (eg, myofascial trigger points; see chap- point to the area where they feel the pain. Pain ter 8). The craniofacial symptoms may be as- should also be marked on pre-prepared draw- sociated with other body pains, and these are ings of extraoral and intraoral regions (see Fig best recorded on a body drawing. 1-1); these are helpful for communicating with the patient and serve as an important reference at a later stage. Pain can be unilateral, mean- Temporal behavior ing on one side of the face, head, or mouth, or Another valuable descriptor is the behavior of bilateral, that is, on both sides. Often pain is pain in relation to time. The temporal behavior unilateral but may change sides from attack to of the pain, once established, may be crucial attack (migraine), whereas in other conditions in diagnosis. One of the essential features of it may predominantly affect one side or even many craniofacial pains is the age of onset; be side-locked (always on the same side). The migraine typically begins early in life, whereas patient should describe, and outline by finger trigeminal neuralgia affects older subjects. pointing, whether the pain is localized or dif- Pain may occur at specific times of the day, fuse. Diffuse implies a large area with ill-defined such as the morning or evening; thus, times

11 1 The Diagnostic Process

of pain onset should be recorded. Moreover, pain onset may be associated with weekly Modes of onset (eg, weekends), monthly (eg, menstruation), or When strong pain develops very rapidly and ag- even yearly (eg, seasonal) events. Pain can be gressively, such as in pulpitis or trigeminal neural- intermittent when it comes and goes, such as gia, it is termed paroxysmal. Pain is evoked when in pulpitis, or continuous when it lasts for long it occurs only after stimulation, for example, cold periods, such as in muscular pain. Episodic application to a tooth with a caries lesion; spon- pain, also termed periodic, appears only during taneous when it occurs on its own with no exter- certain periods, and the patient is otherwise nal stimulus, such as pulpitis; or triggered when pain free. For example, pain appears for a day the pain response is out of proportion to the or two a couple of times in a month, as in mi- stimulus, such as is typical for trigeminal neural- graine, or for a couple of weeks once a year, gia. Pain is termed progressive when it becomes as in cluster headache (see chapters 10 and more severe, or stronger, over time. 11). Pain may become inactive for prolonged periods and be in remission, such as observed in cluster headache and trigeminal neuralgia. Pain intensity Of diagnostic significance is whether the pain Pain intensity is valuable diagnostic informa- wakes the patient from sleep, because this is tion, and thus patients are asked to evaluate related to pain intensity and often specifically how strong their pain feels. A simple and quick to certain diagnoses. way is to ask the patient to assess pain intensi- Pain duration is often included in the clas- ty on a scale of 0 to 10 (a verbal analog scale, sification of orofacial pain syndromes. Masti- where 0 means no pain at all, and 10 is the most catory myofascial pain, for example, may last excruciating pain imagined). The use of a visual from a few hours to the best part of a day, with analog scale, where the patient can mark the a mean of about 5 or 6 hours (see chapter 8). pain intensity, is also useful; a number of such Very short pain attacks—from a few seconds to scales are available. Chapter 3 gives detailed 2 minutes—are characteristic of trigeminal neu- descriptions of the methods for evaluating and ralgia. At the other end of the spectrum, TTHs measuring pain intensity and unpleasantness. may last a few days, though in the chronic form Note, however, that there is tremendous over- they are often continuous. Overlap in pain du- lap between intensities reported for craniofacial ration is common among related facial pain pain syndromes (Fig 1-2). syndromes, such as the trigeminal autonomic cephalalgias (see chapter 11 and Fig 11-12a). A further temporal aspect of pain behavior Pain quality relates to the frequency of pain attacks. Fre- Patients suffering from particular pain syn- quency is the number of attacks over a defined dromes more often use certain descriptive period—per day, week, month, or months and terms. Trigeminal neuralgia presents with pain in very frequent attacks in units of minutes to that is sharp or electric, and other neuropathies hours. As described later, pain may be evoked are characterized by burning pain (Fig 1-3). or initiated by external stimuli, in which case the Neurovascular pain is usually throbbing in na- frequency of pain is related to the frequency of ture, although some forms of dental patholo- the stimulus application. Although specific enti- gies also possess this quality (Fig 1-4). There- ties are associated with a characteristic frequen- fore, we as clinicians try to elucidate specific cy of attacks, there may be significant overlap descriptions from patients with pain by con- (for example, see chapter 11 and Fig 11-12b). ducting a verbal interview or using established Frequency of attacks is easily obtained from questionnaires, such as the McGill Pain Ques- conscientiously kept pain diaries (Form 1-3). tionnaire (see chapter 3).

12 The Pain History

Patient’s name:______On a scale of 0 to 10, when 0 = no pain and 10 = worst pain imaginable, mark your pain for four periods in the day (morning, midday, afternoon, and night [only if it wakes you]).

Pain intensity Medication Remarks

prescribed Day Morning Midday Afternoon Night Side effects, Effect on escape drugs quality of and (no., type) life

date

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28

Form 1-3 Model of a pain diary used in a clinical setting.

13 1 The Diagnostic Process

10

) 9 8 7 6 5 4 ain intensity P 3 2

(10-cm visual analog scale 1 0 Migraine Cluster PH HC IP TN MMP Clinical diagnosis

Fig 1-2 Mean pain severity in various craniofacial pain disorders. PH, paroxysmal hemicrania; HC, hemicrania continua; IP, irreversible pulpitis; TN, trigeminal neu- ralgia; MMP, masticatory myofascial pain.

Craniofacial pain

Neurovascular Musculoskeletal Neuropathic

Throbbing Deep Dermatomal Wakes patient Pressure Burning or electric Autonomic and Muscle tenderness Sensory dysfunction systemic signs Dysfunction

Fig 1-3 Symptomatic, system-based classification of chronic craniofacial pain.

90 80 70 60 50 40 30 20 ercent with throbbing pain P 10 0 Migraine Cluster PH HC IP Clinical diagnosis

Fig 1-4 Percent of patients reporting a throbbing quality in various craniofacial pain disorders. PH, paroxysmal hemicrania; HC, hemicrania continua; IP, irrevers- ible pulpitis.

14 The Pain History

autonomic cephalalgias (see chapter 11) and Aggravating or alleviating factors fibromyalgia (see chapter 8) may be patho- Another part of the pain history is an attempt physiologically related to specific sleep disor- to elucidate if the pain is aggravated by specif- ders.58,59 Pain diaries, where the patients record ic factors. These may be local factors, such as nighttime pain, are often the first sign that they chewing; ingesting cold or hot drinks; or more suffer from disturbed sleep. However, patients generalized stimuli, such as exposure to cold often report getting a full night’s sleep but air, bending down, physical activity, stress, or awakening feeling not rested or unrefreshed. excitement. Certain syndromes are character- This pattern of unrefreshing sleep may aggra- ized by what alleviates or reduces the pain se- vate the pain condition, and a vicious cycle is verity; for example, rest or sleep often alleviates set up. Referral for a sleep study will determine pain for patients with migraine. The response to the nature of the sleep disorder and help for- simple analgesics or specific medications may mulate a more comprehensive management often aid in diagnosis (see chapters 11 and 12). approach. The orofacial pain specialist must be cognizant of the structure, control, and func- tion of normal sleep and the effects of pain- or Impact on daily function and quality stress-related disruption. The relationship be- of life tween pain and sleep is detailed in chapter 5. Pain often interferes with basic orofacial func- tions, such as chewing, speaking, or tooth brush- Associated features ing. Secondary results may include detrimental A number of local or general features consis- dietary changes, social isolation, and dental ne- tently accompany pain attacks. These may be glect with ensuing pathology. Additionally, most localized (as in swelling, redness, sweating, chronic pain states produce an increasingly neg- tearing, rhinorrhea, or ptosis) or generalized ative impact on the patient’s general physical (such as nausea, photophobia, and dizziness). function and quality of life. This may reduce the In addition, sensory changes may be associat- patient’s work capacity and affect the function of ed with the pain complaint. Some patients may the surrounding family members. not be aware of a neurologic deficit, and thus the authors recommend a basic examination of the cranial nerves, outlined in Table 1-3. If Sleep disruption there are findings, the specific modes of senso- Pain-related sleep disorders are very common ry changes are evaluated later, as discussed in and underlie many of the affective and cogni- detail in chapter 3. tive problems in patients with chronic pain.50 Prolonged periods of disturbed sleep induce daytime fatigue, sleepiness, difficulties with Drug history as it pertains to the pain concentration, and reduced coping abilities.51 condition Additionally, disturbed sleep per se may induce Patients often forget the drugs and dosages generalized muscle pain and reduced pain they are taking, so they should bring documen- thresholds and endurance.50 These are import- tation with them on their first visit. The most re- ant factors to consider in the management of liable method is to request a physician’s sum- chronic orofacial pain. mary, but a drug card, medical alert bracelets, Sleep disorders may occur directly because and hospital release notes are also valuable of pain or medical comorbidity.52–55 Acute den- sources of information. Recording what drugs tal conditions, such as irreversible pulpitis or the patient has tried in order to alleviate pain acute dentoalveolar abscess, may cause dis- is imperative. These may be over-the-counter turbed sleep. The association between such drugs or physician-prescribed drugs. Exact dental conditions and sleep is based on the in- dosage, schedule, and duration for each drug tensity of pain and not a specific diagnosis.56,57 will indicate whether the full therapeutic poten- Certain pain syndromes, such as the trigeminal tial was exploited.

15 1 The Diagnostic Process

Table 1-3 Basic cranial nerve examination Test Result Pathway/cranial nerve Group A (Cranial nerves I, II, III, IV, VI, and VIII) Shine a light into the patient’s pupil Tests the pupillary light Afferent is the optic nerve (I) and efferent the (test both sides). reflex: Pupils should oculomotor (III) constrict bilaterally Ask the patient to close his eyes, seal Positive identification Tests olfactory nerve function (II); note that one nostril, and smell coffee, tobacco, of smell patients with colds or allergies may have a or eugenol packed in unmarked reduced ability containers. Ask the patient to seal one ear and Accurate repetition Tests the vestibulocochlear nerve (VIII) whisper numbers contralaterally. Ask the patient to follow your Accurate and smooth Tests the oculomotor (III), trochlear (IV), and finger with his eyes in tracking of finger abducens (VI) nerves the following directions: movements by both eyes simultaneously Group B (Cranial nerves V and VII) Ask the patient to look laterally and Tests the corneal Afferent is the trigeminal nerve and efferent the up with his eyes: gently stimulate the reflex; causes facial cornea with a wisp of cotton wool. immediate closure of the eyelids With his eyes closed, ask the patient Accurate identification Sensory branches of the trigeminal (V) nerve to identify sharp, blunt, and thermal of stimuli and area stimuli in the upper, middle, and lower tested face. Ask the patient to clench teeth. Feel for symmetric Motor branch of the trigeminal (V) nerve contraction of masticatory (eg, masseter) muscles Ask patient to raise his eyebrows, Symmetric movement; Facial (VII) nerve function close his eyes, smile, and whistle. good muscle strength Place sweet, salty, and sour stimuli on Accurate identification Chorda tympani branch of facial nerve the patient’s tongue. Group C (Cranial nerves IX, X, XI, and XII) Ask the patient to rotate his head to Symmetric movement; Accessory (XI) nerve both sides, then raise his shoulders good muscle strength (all against mild manual resistance). Ask the patient to say “aah.” The uvula and soft Glossopharyngeal (IX) nerve palate should be raised symmetrically Ask the patient to perform tongue Hypoglossal (XII) nerve movements.

16 Confirmatory Tests

Listening to the language of pain pain (eg, caries lesions, mucosal erosions, or Patients with similar pain conditions may de- ulcerations) and includes examination modal- scribe their pain in very different terms. This ities such as inspection, probing, palpation, may reflect differences in culture, education, or and percussion. The authors summarize phys- the actual physical experience of pain, no doubt ical findings on a standardized form (see Form influenced by genetic factors. Patients most of- 1-2), though clinicians may want to devise their ten describe their pain in the physical dimen- own form of examination according to person- sion, for example, by severity and quality. Thus, al preferences. a patient with trigeminal neuralgia may relate that the pain is severe and electric, or sharp. On the other hand, some patients may choose Confirmatory Tests terms that describe an emotional dimension; the same patient with trigeminal neuralgia may add Several other tests, in addition to the routine that the pain is unbearable to live with, fright- physical examination, may be required to con- ening, or depressing. This multidimensionality firm or refute the suspected diagnosis. These of pain underlies its definition as an experience may be as simple as the application of a cold rather than as a sensation. The choice of words stimulus to a tooth with suspected pulpitis or to describe pain is therefore important and of- more elaborate sensory testing (see chapter 3). fers an insight into the complete experience Radiographs and other means of imaging are that a patient with pain endures (see chapters still by far the most useful ancillary tests. These 3 and 4). Psychosocial assessment of patients include the simple, relatively cheap, bitewing with pain is therefore important (see chapter or periapical dental radiographs (see chapter 4). The application of questionnaires typically 6) and more sophisticated, neuroimaging tech- used in such assessments is time-consuming niques such as computed tomography (CT) or but may be invaluable in preparing a treatment magnetic resonance imaging (MRI). plan and assessing prognosis. The decision when to refer a patient with chronic orofacial pain for advanced neuroimag- ing is often complex, particularly under current financial constraints in health care systems. Physical Examination Most studies dealing with this issue relate spe- The physical examination of a patient who com- cifically to headache or trigeminal neuralgia, plains of pain aims to identify the source and but the guidelines may be easily adopted for 60–62 cause of pain, that is, the affected structure and orofacial pain in general. Among patients the pathophysiologic process. Routine physical with normal neurologic examinations and head- examination builds on the history to formulate aches diagnosed as migraine or tension type, a differential diagnosis and may require further the prevalence of significant intracranial ab- special tests. normalities on neuroimaging is approximately 63 A routine physical examination of the head 0.2% and 0%, respectively. Undiagnosable and neck should include observation, clinical headaches have a higher prevalence of intracra- examination (eg, palpation), and detection of nial abnormalities, but studies report varying, 63 functional and sensory deviations from the inconsistent figures ranging from 0% to 6.7%. normal. Clinicians should look for facial asym- Positive neurologic findings are intuitively sug- metry, change in color, and deviation or limita- gestive of an intracranial abnormality (see also tion of mouth opening. They should also pal- chapter 12). However, the predictive value of pate cervical and submaxillary lymph nodes, an intracranial abnormality by a positive neuro- parotid and submandibular salivary glands, logic exam is surprisingly low, around 3%; this masticatory and neck muscles, and the tem- is due to the very low initial probability of in- poromandibular joint to detect any abnormality tracranial abnormalities. Patient complaints of in texture, mobility, or tenderness. A routine, neurologic symptoms will significantly increase 63 basic examination of the cranial nerves (see this risk. The absence of findings on a neuro- Table 1-3) should also be performed. An in- logic examination notably decreases (but does traoral examination seeks possible sources of not eliminate) the likelihood of finding a signif-

17 1 The Diagnostic Process

Box 1-2 Indications for neuroimaging in headache

Clear indication • Unexplained abnormal neurologic finding (eg, numbness)

Possible indication • Headache worsened by Valsalva maneuver • Headache causing awakening from sleep • New headache in the older population • Progressively worsening headache or rapidly increasing headache frequency

icant lesion on neuroimaging.63 When ordering scans performed at the ages of 35 to 54 years. neuroimaging, the orofacial pain practitioner These data indicate that risk-reduction efforts should specifically ask that extracranial areas are warranted. be examined (jaws, submandibular space), as Additionally, overtesting adds a large eco- these are often excluded on routine imaging. nomic burden to the health care system. To The indications for advanced neuroimaging help reduce such waste in the United States are shown in Box 1-2. For individual patients and promote physician and patient conversa- with pronounced anxiety, imaging may be in- tions on choosing treatments and tests wisely, dicated to alleviate emotional distress. The nine medical specialty societies have joined the number of studies comparing CT with MRI is American Board of Internal Medicine Founda- limited, but they suggest that MRI may be more tion and Consumer Reports in the first phase sensitive than CT for identifying clinically insig- of the Choosing Wisely campaign.65 These nine nificant abnormalities. However, MRI may not organizations were asked to pick five tests or be more sensitive for identifying clinically sig- treatments within their purview that they be- nificant pathology that is relevant to the cause lieved are overused. The Choosing Wisely of headache.63 Thus, the choice of modality and website (www.choosingwisely.org) lists 45 such the region to be scanned need to be based on a tests and treatments, and eight organizations differential diagnosis. list at least one imaging test.66 The American Headache Society’s board of directors recently made clear recommendations about not per- Choosing wisely forming neuroimaging studies in patients with The use of CT increased threefold from 1993 to stable headaches that meet criteria for migraine 2007, and concerns have been raised over the and not performing CT imaging for headache negative health effects of CT.64 The authors of a when MRI is available, except in emergency risk-assessment study estimated that approxi- settings.67 mately 29,000 future cancers could be related Clearly, organizations that bring together to CT scans performed in the United States orofacial pain experts need to formulate sim- in 2007. The largest contributions were from ilar recommendations. Meanwhile, clinicians scans of the abdomen and pelvis (n = 14,000), are advised to carefully consider the use of chest (n = 4,100), and head (n = 4,000).64 One- confirmatory tests and the cost (monetary and third of the projected cancers were due to healthwise) to benefit ratio of such tests.

18 Establishing a Diagnosis

or inexperienced clinician, the question of what Establishing a Diagnosis to do with all of this information is real. Often, connecting the collected information with a di- Routines in medicine are very effective in that agnosis or a set of criteria in a classification is they add confidence, especially to the inexpe- difficult. rienced; sometimes save time; and ensure a comprehensive gathering of clinical informa- tion. In principle, the diagnosis should follow Diagnosis for beginners the history, physical examination, and ancillary Over the years, the authors have developed a tests. Clinical information gathering is a back- clustering system for diagnostic entities that and-forth process, mainly dictated by the di- is useful for the more difficult diagnostic pro- agnostic process and the possible differential cess of chronic orofacial pain and thus useful diagnoses considered. for trainees and students. The system divides Indeed, an experienced clinician often for- chronic orofacial pain into three main symp- mulates initial diagnostic hypotheses very early tomatic classes: musculoskeletal, neurovas- on in the clinical setting. At a certain point, and cular, and neuropathic (detailed in Fig 1-3 and usually quite early, we start to depart from the Box 1-3). The authors advise the beginner to routine and to consider diagnostic hypothe- examine these entities and the cluster of signs ses. We start to test these hypotheses by ask- and symptoms relevant for each class of these ing specific questions. The difference is that diagnostic entities. Then proceed to Table 1-4 while routine questions expect an open-ended for a description of the diagnostic process gen- answer to such questions as “Where do you erated by hypotheses based on pain location, feel your pain?” most hypothesis-generated and then go to Table 1-5 for the diagnostic pro- questions aim at a closed-ended yes or no an- cess based on the temporal behavior and char- swer. For example, asking “Does bending your acteristics of the pain. This system proceeds head aggravate pain?” is useful when a pa- from signs and symptoms presented by the tient is suspected to have sinusitis. “Does the patient to the disease process hypothesized tooth react painfully to a cold stimulus?” may by the clinician (ie, diagnostic hypothesis). This be asked when a caries lesion is suspected allows the beginner to get an initial feel for the in a vital tooth. The answer expected to such diagnosis and see which family of entities it be- questions is yes or no. If the answer, whether longs to. to an oral question or a physical test, satisfies After considering a diagnosis, it is legiti- the hypothesis, the examiner usually proceeds mate to keep testing it by gathering further in- with another hypothesis-generated question. If formation. In reference to points addressed in the answer leads to a dead end, however, clini- the “Information critical for hypothesis testing” cians often return to the routine methodology. column of Tables 1-4 and 1-5, further specific Ultimately, we cluster enough positive pieces of information is requested at all levels: history, information to confirm our hypothesis (diagno- physical examination, and ancillary tests. The sis) and usually some negative pieces of infor- ability to start the diagnostic process from mation that enable us to refute other possible pain location (see Table 1-4) or from pain char- diagnoses. acteristics (see Table 1-5) demonstrates the Clustering of information is a useful tool in versatility of the interview method and allows the decision-making process in that it reduces the clinician to cross-check the hypothesis the number of fragments of information and fa- generation in more than one way. The authors cilitates the process. The specific clustering of recommend that the reader refer back to this signs, symptoms, and other information leads method of diagnosing chronic orofacial pain to a diagnosis based on classification systems, when reading subsequent chapters, especial- as discussed earlier. ly the chapters dealing with chronic orofacial However, gathering information on its own pain of musculoskeletal, neurovascular, or does not make a diagnosis. For the beginner neuropathic origin.

19 1 The Diagnostic Process

Typical clusters of signs and symptoms in the main chronic Box 1-3 orofacial pain entities

1. Musculoskeletal orofacial pain Temporomandibular joint (TMJ) pain • Pain fairly localized to TMJ area • Click/crepitating of TMJ • Deviation of mouth opening toward affected joint • TMJ painful on palpation • Pain on function (biting on contralateral side to affected TMJ)

Masticatory myofascial pain • Pain, mostly unilateral, at angle of mandible and front of ear (diffuse) • Masticatory muscle tenderness on palpation, mostly on affected side • Jaw dysfunction (limited opening, tiredness on chewing) • Pain on function (eg, yawning, chewing, talking)

Tension-type headache • Bilateral pain at temples and occipital areas • Pain is pressing and annoying • Pain is periodic or chronic • Anorexia • Nausea

2. Neurovascular craniofacial pain Migraine • Strong, unilateral headache • Pain is throbbing • Pain is periodic (lasting a day or two, a couple of times a month) • Occasional waking from sleep toward morning (REM locked) • Photophobia/phonophobia • Nausea and vomiting • Occasional tearing • Patient seeks rest in a dark quiet place

Cluster headache • Periorbital, unilateral, very strong, throbbing pain • Clusters of active periods of pain (6–10 weeks) mostly once a year • At active period, 1 to 2 attacks per 24 hours, with clockwise regularity • Typical attack lasts 45–60 minutes • Occasional waking from sleep (REM locked) • Tearing, one eye on affected side • Rhinorrhea, one nostril on affected side • Redness, ptosis, and miosis of eye on affected side (possible) • Patient paces around restlessly

Chronic paroxysmal hemicrania • Periorbital and temporal, unilateral, strong pain • Short (lasting only minutes) paroxysmal pain attacks • Occasional waking from sleep • Tearing, conjunctival injection, one eye on affected side • Rhinorrhea, one nostril on affected side • Head movement may trigger pain

20 Establishing a Diagnosis

SUNCT (short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing) • Periorbital, unilateral, severe pain • Paroxysmal, short (lasting seconds) attacks • Pain precipitated by touch of eyebrow • Conjunctival injection, tearing

Neurovascular orofacial pain • Midface, perioral, and intraoral pain • Spontaneous or evoked pain (mostly by cold food ingestion) • Occasional swelling or redness of cheek • Waking from sleep • Nausea • Tearing, one eye on affected side (possible) • Pain mostly periodic but may be chronic

Hemicrania continua • Unilateral, moderate-intensity headache with no side shifts • Chronic (lasting more than 3 months), daily nonremitting • Rare waking from sleep • Mild tearing, one eye on affected side • Mild rhinorrhea, one nostril on affected side • Occasional eye redness, ptosis, and miosis on affected side

3. Neuropathic orofacial pain Trigeminal neuralgia • Unilateral pain in the trigeminal nerve area (mostly 2nd and 3rd divisions) • Paroxysmal, electriclike, very short (lasting seconds), strong pain • Pain attack accompanied by facial tic • Pain triggered by light touch, vibration, and other nonpainful stimuli • After triggering, there is a refractory period • No sensory deficit

Traumatic neuropathies (CRPS-I/II) • Pain location associated with history of trauma • Pain continuous, mostly burning quality • Allodynia • Edema/redness • Trophic changes (mostly in CRPS II) • Sensory deficit (in CRPS II) • Dysesthesia (in CRPS II)

REM, rapid eye movement; CRPS, complex regional pain syndrome.

21 1 The Diagnostic Process

Diagnostic process and hypothesis generation Table 1-4 based on pain location Location Information critical for (unilateral) Diagnostic hypothesis hypothesis testing Frontotemporal* Migraine Pain attack duration Hemicrania continua Patterns of periodicity Photo- and/or phonophobia Nausea Orbital and Cluster headache Pain attack duration periorbital Paroxysmal hemicrania Attacks/day SUNCT Periodicity Tearing, rhinorrhea SUNCT triggered by touch Preauricular, angle Temporomandibular joint (TMJ) pain Aggravated by chewing of mandible Masticatory muscle pain Mouth opening dysfunction TMJ tenderness, click Masticatory muscle tenderness Midface, perioral, Trigeminal neuralgia Attack duration or intraoral Neurovascular orofacial pain (NVOP) Triggered by touch, vibration Evoked by cold/hot foods Tearing, rhinorrhea *If the pain is bilateral, consider tension-type headache. SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.

Diagnostic process and hypothesis generation based on temporal pain Table 1-5 behavior and characteristics Temporal pain behavior Information critical for and characteristics Diagnostic hypothesis hypothesis testing Short, paroxysmal Trigeminal neuralgia Pain location Paroxysmal hemicrania Duration of pain attack SUNCT Triggering/evoking stimuli Autonomic signs Wakes from sleep Periodic, throbbing Migraine Pain location Cluster headache Duration of pain attack Neurovascular orofacial pain Periodicity Autonomic signs Nausea Continuous, pressing Tension-type headache (TMJ) Pain location, laterality Temporomandibular joint pain Aggravates by chewing Masticatory muscle pain Mouth opening dysfunction Hemicrania continua TMJ tenderness, click Complex regional pain syndrome Masticatory muscle tenderness (type I or II) History of trauma Sensory abnormality SUNCT, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing.

22 The Patient with Pain

impaired in certain ethnic groups, and some of The Patient with Pain this effect may be related to increased stress.70 Gene regulation depends on the function of Patients with undiagnosed pain may worry regulatory elements that turn genes on and off that they have cancer or some other threat- at the right time. Regulatory elements are spe- ening disease. Prospective studies suggest a cific DNA sequences in the vicinity of the gene relationship between psychologic distress and to be regulated; others may be DNA-binding pain, which may operate both ways (see chap- proteins or micro-RNA molecules that use ter 4). A high level of psychologic distress is base-pair specificity to modulate gene ex- often a predictor of the onset of future pain or pression after transcription. Alterations to the the development of chronic pain. Conversely, structure of chromatin will modify gene ex- ongoing orofacial pain is often associated with pression and subsequently the phenotype. psychologic distress.68 Research shows that These changes, which are independent of al- patients with chronic craniofacial pain suffer terations to the DNA sequence, are called epi- from psychologic distress, increased depres- genetic changes, which include DNA methyl- sion, impaired social performance, and de- ation, histone methylation, repressive protein creased quality of life (see chapters 7 and 9 to complexes, and RNA interference. Covalent 12). Thus, patients with chronic orofacial pain modification of DNA by methylation is a criti- develop maladaptive or illness behavior pat- cal epigenetic mechanism that regulates gene terns68 that are important factors affecting their expression. Increased methylation will inhibit management and prognosis. gene expression, and decreased methylation Patients differ in many respects that influ- will increase it. Significant evidence supports ence diagnostic considerations, such as re- the role of epigenetic modification after inju- sponses to pain medications, attitudes toward ry and its involvement in the onset of chronic health care, and behavioral responses to chron- pain.71–73 Clearly, genetic considerations will ic pain. In the sections that follow, the effects become integral to diagnostic and therapeutic of three important factors—genetics, sex, and approaches to chronic pain. culture and ethnicity—are discussed. Sex Genetics and epigenetics Extensive, and often inconsistent, reports The sequencing of the human genome has have examined the effects of sex on the epi- elucidated the presence of 30,000 to 40,000 demiology of pain syndromes, pain thresholds, human genes. Some of these genes and pro- and analgesic responses.74,75 Additionally, the tein end-products will emerge as new thera- menstrual phase may affect the efficacy of the peutic targets for chronic pain. For some pain endogenous pain modulatory system.76 Wom- syndromes, information is available on genetic en suffer significantly more from migraines, polymorphisms that may affect disease oc- TTHs, facial pains, fibromyalgia, and TMDs.77–81 currence; this area is covered in chapters 7, 9, In general, women do not seek treatment for 10, and 11. Information concerning genetically orofacial pain significantly more frequently than controlled drug toxicity and common adverse men do.82 However, for TMDs, women usual- drug reactions is available on an individual ba- ly demand more care than men do,83 probably sis. Genetically governed interindividual differ- because they have more severe symptoms. ences are found in drug-transport proteins and Both hormone replacement therapy and use of drug targets (receptors), which may alter the oral contraceptives have been associated with pharmacokinetics and pharmacodynamics of increased risk of TMD84,85 (see chapter 8). The a variety of drugs. For example, the analgesic use of oral contraceptives has been shown to potency of morphine is partly dictated by vari- both improve and worsen headaches, depend- ations in the expression of μ-opioid receptors. ing on the hormones used, duration of treat- Polymorphisms in this receptor lead to inter­ ment, and dosages.86 Preliminary data indicate individual differences in responses to pain and that menopause can affect pain, depending on its relief by opioid drugs.69 Pain modulation is the painful condition experienced.87

23 1 The Diagnostic Process

Under experimental conditions, women deficiency) do not exist, but these traits cannot consistently demonstrate a lower pain thresh- solely define ethnicity. old, often affected by the stage of the menstru- Cultural and social factors are the founda- al cycle and by exogenous hormones such as tion for the expression and management of oral contraceptives.88 Injection of capsaicin into pain.95 They affect patients’ experience of pain the forehead induced trigeminal sensitization as well as their behavioral responses, seeking and evoked sex-specific sensory and vasomo- of health care, and adherence to treatment.97 In tor responses; menstruating women generally a multiracial environment, we as clinicians must showed the strongest manifestations.89 Postex- understand these factors and attempt to posi- traction pain and pain under experimental con- tively modify the way we practice pain medi- ditions in women responds better to opioid cine. Examples that highlight the influence of therapy than it does in men.90 However, men culture and beliefs on the experience and inter- and women may differ in their response to non- pretation of pain include the reliance on religion steroidal anti-inflammatory drugs, and women to cope with pain in some ethnic groups95,96 and enjoy less analgesia with ibuprofen than men differences in the use of local anesthetic for do.91 Other studies found no sex-based dif- dental treatment.98 Pain sensitivity, secondary ferences related to ibuprofen use or the lev- hyperalgesic area, and pressure pain thresh- el of induced placebo analgesia after tooth olds after capsaicin injection to the forehead extraction.92,93 were assessed in South Indians and whites.99 The practical applications of sex differences South Indians showed significantly greater pain include menstrual-related changes in pain sen- responses compared with whites. Ethnic differ- sitivity that may be associated with increased ences in pain tolerance reflect traits in the affec- analgesic use. Epidemiologic data continue tive dimension of pain; these differences are not to accumulate concerning pain syndromes in innate but learned and may even be modified women and pharmacologic traits particular to by the environment at later stages.96 However, each sex; clearly, these are areas that will aid no difference has been observed between eth- pain physicians. nic groups in the amounts of self-administered analgesia for acute pain.100 After consultation for pain management, patients reported signif- Culture and ethnicity icant pain relief, regardless of race or ethnic- In 1969, Mark Zborowski highlighted the role ity.101 Despite these pain decreases, Latinos of ethnicity in a person’s reaction to pain in were 62% more likely than whites to report pain the classic book People in Pain,94 which deals at discharge and follow-up.101 with the attitudes and reaction to pain in three American ethnic groups and points to striking differences. More recent research examines Treatment racial and ethnic variability affecting the pain experience.95,96 The initial aim of the diagnostic process is to The terms culture, ethnicity, and race are of- initiate the patient on a treatment plan; the ulti- ten used interchangeably, probably because it mate, but elusive, aim is the eradication of pain, is difficult to accurately define them. Because which may involve multiple modalities. Patients of the massive population migration, intermar- with acute pain are usually alarmed and anxious riage, and genetic polymorphisms, populations by this sudden, mostly unexpected, change in such as Africans, whites, and Asians are more their state of well-being and need a lot of re- genetically heterogenous within than across assurance. An accurate diagnosis, empathetic groups. Indeed, anthropologists and biologists explanation, and effective treatment are import- are increasingly defining race as a social con- ant to reassure patients and obtain their confi- struct and not a scientific category.96 This is dence. Treatment of acute pain often includes not to say that genetically distinct physiologic physical intervention, such as tooth pulp extir- or medical traits in ethnic populations (eg, Tay- pation or use of analgesics (see chapters 6, 7, Sachs or drug metabolism conditions such as and 15). Dentists do this almost every day, and glucose-6-phosphate dehydrogenase enzyme the vast majority of patients enjoy rapid and

24 Follow-Up complete relief from acute dental pain within a way patients respond to pain and its manage- short time. ment, and we must therefore understand how Chronic pain, as its name implies, is long clinicians and patients interact to influence standing and many times associated with co- health care delivery. As clinicians, we should be morbidities such as negative changes in func- aware that we tend to have more empathy for tion, drug abuse, psychosocial dysfunction, the pain suffered by persons of our own race and depression (see chapters 4 and 8 to 12). than for those of another race.104 Consequently, the aims of therapy in chronic or recurrent pain cannot be limited to the allevia- tion of pain but must include the restoration of Outcomes quality of life and function as well as the preven- tion or elimination of drug abuse. Chronic oro- How do we define success in the treatment facial pain is difficult to eradicate, particularly in of pain? Pain is an individual experience, so a certain syndromes such as traumatic neuropa- successful outcome is also an individual, highly thies, which is why we refer to the management personalized result. Some patients with a re- of chronic orofacial pain rather than its treat- duction of more than 50% in pain intensity af- ment. The goal of pain management, which is ter permanent ingestion of psychotropic drugs often defined as more than a 50% reduction in may be dissatisfied, unhappy, and incapable of pain intensity or frequency, must be explained maintaining normal employment. On the other to patients, as this level of improvement is like- hand, a patient may be able to function nor- ly way below the patient’s initial expectations. mally after achieving less than 50% reduction Furthermore, results may not be obtained as in pain intensity obtained with physiotherapy quickly as patients would wish; multiple lengthy and cognitive behavioral therapy (see chapters drug trials, prolonged physiotherapy, and psy- 4 and 8). Just as we have come to appreciate chologic interventions are often needed before that pain is a complex and individual experi- a reasonable, successful result can be attained. ence, therapeutic outcome needs to assess a broader spectrum, including such factors as restoration of function and psychosocial sta- tus. In a highly simplified paradigm, we need Provider Characteristics to balance the patient’s expectations with the and Analgesic Prescription physician’s possibilities. A more realistic model appreciates that the patient’s expectations are Increasingly, researchers are recognizing the a complex result of a painful experience within importance of identifying factors that influence a context of cultural and ethnic influences, cur- health care workers in their decision-making rent employment, views on health and disease, process. Significant differences were shown to and other variables. occur between the amounts of analgesia pre- scribed to ethnic subgroups.100 Among veterans younger than 65 years who reported moderate Follow-Up to high levels of chronic, non–cancer-related pain, blacks were less likely to be prescribed The use of pain diaries is very useful for opioids than whites.102 Eliminating racial dif- follow-up, for assessing treatment results, and ferences in pain treatment therefore remains a often for confirming a diagnosis. To ensure challenge. Clearly, ethnocultural background compliance, the authors keep their pain diary may influence a clinician’s assessment of pain as simple as possible (see Form 1-3), but this intensity in patients, and minorities remain at can be modified to meet individual needs. The risk for inadequate pain control.95 patient records pain intensity and its effect on A recent review highlights further factors in- quality of life on a numeric scale from 0 to 10 at volved in analgesic prescription by health care different times of the day (including night if the providers.103 These effects include medical spe- pain wakes the patient from sleep). The diary cialty, age, experience, and sex interplays.103 also records dosages of prescribed drugs, es- Cultural and demographic factors affect the cape drugs if used, and adverse pharmacologic

25 1 The Diagnostic Process

effects. A 28-day diary is sufficient to allow the discussed in detail in chapter 4, offers an effec- authors to adjust treatment according to pain tive mode for improving coping skills. Of special response and side effects. Patients’ reaction to concern are patients with trauma-related pain, the pain diary is usually very positive; they be- who often suffer from post-traumatic stress dis- lieve their pain symptoms are taken seriously order and need early psychologic intervention. and are reassured by the attention given to their response to therapy. The pain diary is also essential in controlling The Pain Clinic drug abuse. Patients with chronic pain often abuse many drugs, some prescribed and some Pain is one of the prime reasons people seek obtained over the counter. Often drugs pre- medical attention. In most instances of orofa- scribed in the past are still taken and added cial pain, the patient’s main route is to look for to those currently used; unless specifically in- help at a dental clinic or see the family physi- structed, patients may not stop taking previous- cian. In most cases, especially for those with ly prescribed medications. The recording of es- acute pain, patient management and treatment cape drugs in the diary (usually analgesics used results are easily attained. However, when the to control breakthrough pain), in addition to the situation is complicated, especially given the prescribed medications, facilitates the detection anatomical density of the orofacial region, a visit of drug abuse. Drug consumption in response to an orofacial pain clinic becomes a necessity. to breakthrough pain is a learned response that Physicians and staff at a pain clinic approach may lead to dependence. Reviewing the pattern chronic pain as a disease and offer expertise and amount of escape drug used allows the on the pathophysiology of pain, pain medica- authors to advise patients on adequate sched- tion for acute and chronic pain, and alternative uling and helps break the habit of taking addi- treatment options (see chapters 6, 13, and 15 tional medications. This is achieved by shifting to 17). An additional strength of the pain clinic the patient from on-demand to per-schedule is its ability to use a multidisciplinary team ap- consumption of the escape drug and gradually proach that involves other professionals, such decreasing the amount consumed. As a rule, for as psychologists and physiotherapists. The chronic pain it is always advisable to prescribe concept of the pain clinic is not new and has medications per schedule rather than per de- developed over the years from a center offer- mand, because the latter usually leads to more ing management alternatives for prediagnosed drug abuse and dependence. patients (eg, intrathecal injections, regional blocks, surgical interventions) to a center that diagnoses, manages, and follows up patients in pain. Prognosis and Long-Term An orofacial pain clinic is therefore involved Management in the diagnostic process and management of craniofacial pain. Although pain clinics rely Although we as clinicians aim to eradicate or heavily on pharmacotherapy, other modali- alleviate all pain, we are a long way from opti- ties are performed as appropriate, including mal patient care. Some of the best drugs offer muscle trigger-point injection, arthrocentesis substantial relief to some patients, but not all of the temporomandibular joint, acupuncture, patients will be pain free despite our treatment hypnotherapy, night guards, and physiother- (see clinical chapters and chapter 16). For many apy. Consultations with neurosurgery, neurol- patients, particularly those who do not respond ogy, otolaryngology, and other specialists are well to therapy, we must offer means for better common, and patients may be referred for coping with their agony and despair. We can psychiatric evaluation and cognitive behavioral help the patient to increase adaptive skills in therapy. The intimate relationship between the order to minimize pain-related stress and avoid pain clinic and other members of the medical unnecessary illness behavior by means of cog- community has become a two-way channel for nitive behavioral therapy and other psychologic patient referral, communication, and constant pain management approaches. This approach, enrichment of knowledge.

26 References

19. Dodick DW. Indomethacin-responsive headache syn- References dromes. Curr Pain Headache Rep 2004;8:19–26. 20. Anderton LA. Concepts and classification of disease. 1. Sharav Y, Benoliel R. Primary vascular-type craniofa- In: Demeny P, McNicoll G (eds). Encyclopedia of Pop- cial pain. Compend Contin Educ Dent 2001;22:119– ulation. New York: MacMillan Reference, 2003:247– 122;124–126;128. 250. 2. Benoliel R, Sharav Y. Accurate diagnosis of facial 21. Sprenger T, May A. Advanced neuroimaging for the pain. Cephalalgia 2006;26:902. study of migraine pathophysiology. Pain Clinical Up- 3. Benoliel R, Birman N, Eliav E, Sharav Y. The In- dates, vol 6. Seattle: International Association for the ternational Classification of Headache Disorders: Study of Pain, 2012. Accurate diagnosis of orofacial pain? Cephalalgia 22. Pearce JM. Disease, diagnosis or syndrome? Pract 2008;28:752–762. Neurol 2011;11:91–97. 4. Zebenholzer K, Wöber C, Vigl M, Wessely P, Wöber- 23. Aggarwal VR, McBeth J, Zakrzewska JM, Lunt M, Bingöl C. Facial pain and the second edition of the Macfarlane GJ. The epidemiology of chronic syn- International Classification of Headache Disorders. dromes that are frequently unexplained: Do they Headache 2006;46:259–263. have common associated factors? Int J Epidemiol 5. Zebenholzer K, Wöber C, Vigl M, Wessely P, Wöber- 2006;35:468–476. Bingöl C. Facial pain in a neurological tertiary care 24. Aggarwal VR, McBeth J, Zakrzewska JM, Macfarlane centre—evaluation of the International Classification GJ. Unexplained orofacial pain—Is an early diagnosis of Headache Disorders. Cephalalgia 2005;25:689– possible? Br Dent J 2008;205:E6. 699. 25. Olesen J, Lipton RB. Classification of headache. In: 6. Headache Classification Subcommittee of the Inter- Olesen J, Goadsby PJ, Ramadan NM, Tfelt-Hansen national Headache Society. The international classi- P, Welch KMA (eds). The Headaches, ed 2. Philadel- fication of headache disorders, 3rd edition (beta ver- phia: Lippincott Williams & Wilkins, 2006:9–25. sion). Cephalalgia 2013;33:629–808. 26. Nixdorf DR, Drangsholt MT, Ettlin DA, et al. Classifying 7. Gaskin DJ, Richard P. The economic costs of pain in orofacial pains: A new proposal of taxonomy based the United States. J Pain 2012;13:715–724. on ontology. J Oral Rehabil 2012;39:161–169. 8. Salter MW. Deepening understanding of the neural 27. Billis E, McCarthy CJ, Gliatis J, Gittins M, Papandreou substrates of chronic pain. Brain 2014;137:651–653. M, Oldham JA. Inter-tester reliability of discriminato- 9. McMillan AS, Wong MC, Zheng J, Lam CL. Preva- ry examination items for sub-classifying non-specific lence of orofacial pain and treatment seeking in Hong low back pain. J Rehabil Med 2012;44:851–857. Kong Chinese. J Orofac Pain 2006;20:218–225. 28. Clarke C, Lindsay DR, Pyati S, Buchheit T. Resid- 10. Macfarlane TV, Blinkhorn AS, Davies RM, Kincey J, ual limb pain is not a diagnosis: A proposed algo- Worthington HV. Oro-facial pain in the community: rithm to classify postamputation pain. Clin J Pain Prevalence and associated impact. Community Dent 2013;29:551-562. Oral Epidemiol 2002;30:52–60. 29. Köseoglu E, Naçar M, Talaslioglu A, Cetinkaya F. Epi­ 11. Ng KF, Tsui SL, Chan WS. Prevalence of com- demiological and clinical characteristics of migraine mon chronic pain in Hong Kong adults. Clin J Pain and tension type headache in 1146 females in Kay- 2002;18:275–281. seri, Turkey. Cephalalgia 2003;23:381–388. 12. Isong U, Gansky SA, Plesh O. Temporomandibular 30. Gupta R, Bhatia MS. Comparison of clinical charac- joint and muscle disorder-type pain in U.S. adults: teristics of migraine and tension type headache. Indi- The National Health Interview Survey. J Orofac Pain an J Psychiatry 2011;53:134–139. 2008;22:317–322. 31. Mongini F, Ciccone G, Deregibus A, Ferrero L, Mon- 13. Koopman JS, Dieleman JP, Huygen FJ, de Mos M, gini T. Muscle tenderness in different headache Martin CG, Sturkenboom MC. Incidence of facial pain types and its relation to anxiety and depression. Pain in the general population. Pain 2009;147:122–127. 2004;112:59–64. 14. Renton T, Durham J, Aggarwal VR. The classification 32. Stuginski-Barbosa J, Macedo HR, Bigal ME, Speciali and differential diagnosis of orofacial pain. Expert Rev JG. Signs of temporomandibular disorders in mi- Neurother 2012;12:569–576. graine patients: A prospective, controlled study. Clin J 15. de Leeuw R, Klasser G (eds). Orofacial Pain: Guide- Pain 2010;26:418–421. lines for Assessment, Diagnosis and Management, 33. Chabriat H, Danchot J, Michel P, Joire JE, Henry P. ed 5. Chicago: Quintessence, 2013. Precipitating factors of headache. A prospective study 16. Schiffman E, Ohrbach R, Truelove E, et al. Diagnostic in a national control-matched survey in migraineurs Criteria for Temporomandibular Disorders (DC/TMD) and nonmigraineurs. Headache 1999;39:335–338. for clinical and research applications: Recommenda- 34. Look JO, Schiffman EL, Truelove EL, Ahmad M. Reli- tions of the International RDC/TMD Consortium Net- ability and validity of Axis I of the Research Diagnostic work and Orofacial Pain Special Interest Group. J Oral Criteria for Temporomandibular Disorders (RDC/TMD) Facial Pain Headache 2014;28:6–27. with proposed revisions. J Oral Rehabil 2010;37:744– 17. Benoliel R, Eliav E, Sharav Y. Classification of chronic 759. orofacial pain: Applicability of chronic headache crite- 35. Dworkin SF, LeResche L. Research diagnostic criteria ria. Oral Surg Oral Med Oral Pathol Oral Radiol Endod for temporomandibular disorders: Review, criteria, ex- 2010;110:729–737. aminations and specifications, critique. J Cranioman- 18. Silberstein SD. Chronic daily headache. J Am Osteo- dib Disord 1992;6:301–355. path Assoc 2005;105:23S–29S.

27 1 The Diagnostic Process

36. Eversole LR, Machado L. Temporomandibular joint in- 52. Kelman L, Rains JC. Headache and sleep: Examina- ternal derangements and associated neuromuscular tion of sleep patterns and complaints in a large clinical disorders. J Am Dent Assoc 1985;110:69–79. sample of migraineurs. Headache 2005;45:904–910. 37. Fillingim RB, Ohrbach R, Greenspan JD, et al. Po- 53. Nicholson B, Verma S. Comorbidities in chronic neu- tential psychosocial risk factors for chronic TMD: De- ropathic pain. Pain Med 2004;5(1, suppl):S9–S27. scriptive data and empirically identified domains from 54. Sabatowski R, Gálvez R, Cherry DA, et al. Pregabalin the OPPERA case-control study. J Pain 2011;12(sup- reduces pain and improves sleep and mood distur- pl 11):T46–T60. bances in patients with post-herpetic neuralgia: Re- 38. Komiyama O, Obara R, Uchida T, et al. Pain intensi- sults of a randomised, placebo-controlled clinical trial. ty and psychosocial characteristics of patients with Pain 2004;109:26–35. burning mouth syndrome and trigeminal neuralgia. J 55. Zelman DC, Brandenburg NA, Gore M. Sleep impair- Oral Sci 2012;54:321–327. ment in patients with painful diabetic peripheral neu- 39. Porto F, de Leeuw R, Evans DR, et al. Differences in ropathy. Clin J Pain 2006;22:681–685. psychosocial functioning and sleep quality between 56. Benoliel R, Eliav E, Sharav Y. Self-reports of idiopathic continuous orofacial neuropathic pain pa- pain-related awakenings in persistent orofacial pain tients and chronic masticatory muscle pain patients. patients. J Orofac Pain 2009;23:330–338. J Orofac Pain 2011;25:117–124. 57. Sharav Y, Leviner E, Tzukert A, McGrath PA. The spa- 40. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome tial distribution, intensity and unpleasantness of acute measures for chronic pain clinical trials: IMMPACT dental pain. Pain 1984;20:363–370. recommendations. Pain 2005;113:9–19. 58. Moldofsky HK. Disordered sleep in fibromyalgia and 41. Turner JA, Dworkin SF. Screening for psychosocial related myofascial facial pain conditions. Dent Clin risk factors in patients with chronic orofacial pain: North Am 2001;45:701–713. Recent advances. J Am Dent Assoc 2004;135:1119– 59. Rains JC, Poceta JS. Sleep-related headache syn- 1125. dromes. Semin Neurol 2005;25:69–80. 42. Longo DL, Fauci AS, Kasper DL, Hauser SL, James- 60. Sandrini G, Friberg L, Janig W, et al. Neurophysiolog- on JL, Loscalzo J. The practice of medicine. In: Lon- ical tests and neuroimaging procedures in non-acute go DL, Fauci AS, Kasper DL, Hauser SL, Jameson headache: Guidelines and recommendations. Eur J JL, Loscalzo J (eds). Harrison’s Principles of Internal Neurol 2004;11:217–224. Medicine, ed 18. New York: McGraw Hill Medical, 61. Lester MS, Liu BP. Imaging in the evaluation of head- 2012:2–8. ache. Med Clin North Am 2013;97:243–265. 43. Maixner W, Greenspan JD, Dubner R, et al. Poten- 62. Abrams BM. Factors that cause concern. Med Clin tial autonomic risk factors for chronic TMD: Descrip- North Am 2013;97:225–242. tive data and empirically identified domains from the 63. Frishberg BM, Rosenberg JH, Matchar DB, et al. OPPERA case-control study. J Pain 2011;12(suppl Evidence-based guidelines in the primary care set- 11):T75–T91. ting: Neuroimaging in patients with nonacute head- 44. Slade GD, Conrad MS, Diatchenko L, et al. Cytokine ache. Am Acad Neurol 2000:3–35. biomarkers and chronic pain: Association of genes, 64. Berrington de González A, Mahesh M, Kim KP, et al. transcription, and circulating proteins with temporo- Projected cancer risks from computed tomographic mandibular disorders and widespread palpation ten- scans performed in the United States in 2007. Arch derness. Pain 2011;152:2802–2812. Intern Med 2009;169:2071–2077. 45. Smith SB, Maixner DW, Greenspan JD, et al. Potential 65. Cassel CK, Guest JA. Choosing wisely: Helping phy- genetic risk factors for chronic TMD: Genetic associ- sicians and patients make smart decisions about their ations from the OPPERA case control study. J Pain care. JAMA 2012;307:1801–1802. 2011;12(suppl 11):T92–T101. 66. Rao VM, Levin DC. The overuse of diagnostic imag- 46. De Luca GC, Bartleson JD. When and how to in- ing and the Choosing Wisely Initiative. Ann Intern Med vestigate the patient with headache. Semin Neurol 2012;157:574–576. 2010;30:131–144. 67. Loder E, Weizenbaum E, Frishberg B, Silberstein 47. Loder E, Rizzoli P. Biomarkers in migraine: Their S, American Headache Society Choosing Wisely promise, problems, and practical applications. Head- Task Force. Choosing wisely in headache medicine: ache 2006;46:1046–1058. The American Headache Society’s list of five things 48. Montagna P, Cevoli S, Marzocchi N, et al. The ge- physicians and patients should question. Headache netics of chronic headaches. Neurol Sci 2003;24(2, 2013;53:1651–1659. suppl):S51–S56. 68. Macfarlane TV, Kincey J, Worthington HV. The 49. Rossi P, Vollono C, Valeriani M, Sandrini G. The contri- association between psychological factors and bution of clinical neurophysiology to the comprehen- oro-facial pain: A community-based study. Eur J Pain sion of the tension-type headache mechanisms. Clin 2002;6:427–434. Neurophysiol 2011;122:1075–1085. 69. Uhl GR, Sora I, Wang Z. The mu opiate receptor as a 50. Moldofsky H. Sleep and pain. Sleep Med Rev candidate gene for pain: Polymorphisms, variations in 2001;5:385–396. expression, nociception, and opiate responses. Proc 51. Brousseau M, Manzini C, Thie N, Lavigne G. Under- Natl Acad Sci USA 1999;96:7752–7755. standing and managing the interaction between sleep and pain: An update for the dentist. J Can Dent Assoc 2003;69:437–442.

28 References

70. Mechlin MB, Maixner W, Light KC, Fisher JM, Girdler 88. Fillingim RB, Ness TJ. Sex-related hormonal influenc- SS. African Americans show alterations in endoge- es on pain and analgesic responses. Neurosci Biobe- nous pain regulatory mechanisms and reduced pain hav Rev 2000;24:485–501. tolerance to experimental pain procedures. Psycho- 89. Gazerani P, Andersen OK, Arendt-Nielsen L. A hu- som Med 2005;67:948–956. man experimental capsaicin model for trigeminal 71. Géranton SM. Targeting epigenetic mechanisms for sensitization. Gender-specific differences. Pain pain relief. Curr Opin Pharmacol 2012;12:35–41. 2005;118:155–163. 72. Denk F, McMahon SB. Chronic pain: Emerging ev- 90. Fillingim RB. Sex differences in analgesic responses: idence for the involvement of epigenetics. Neuron Evidence from experimental pain models. Eur J An- 2012;73:435–444. aesthesiol Suppl 2002;26:16–24. 73. Buchheit T, Van de Ven T, Shaw A. Epigenetics and 91. Walker JS, Carmody JJ. Experimental pain in healthy the transition from acute to chronic pain. Pain Med human subjects: Gender differences in nocicep- 2012;13:1474–1490. tion and in response to ibuprofen. Anesth Analg 74. Aloisi AM, Bonifazi M. Sex hormones, central nervous 1998;86:1257–1262. system and pain. Horm Behav 2006;50:1–7. 92. Averbuch M, Katzper M. A search for sex differ- 75. Bartley EJ, Fillingim RB. Sex differences in pain: A ences in response to analgesia. Arch Intern Med brief review of clinical and experimental findings. Br J 2000;160:3424–3428. Anaesth 2013;111:52–58. 93. Averbuch M, Katzper M. Gender and the placebo 76. Rezaii T, Hirschberg AL, Carlström K, Ernberg M. The analgesic effect in acute pain. Clin Pharmacol Ther influence of menstrual phases on pain modulation in 2001;70:287–291. healthy women. J Pain 2012;13:646–655. 94. Zborowski M. People in Pain. San Francisco: Jossey- 77. Breslau N, Rasmussen BK. The impact of migraine: Bass, 1969. Epidemiology, risk factors, and co-morbidities. Neu- 95. Green CR, Anderson KO, Baker TA, et al. The un- rology 2001;56(1, suppl):S4–S12. equal burden of pain: Confronting racial and ethnic 78. Rasmussen BK. Epidemiology of headache. Cepha- disparities in pain. Pain Med 2003;4:277–294. lalgia 1995;15:45–68. 96. Wachholtz AB, Pearce MJ. Does spirituality as a cop- 79. Rauhala K, Oikarinen KS, Järvelin MR, Raustia AM. ing mechanism help or hinder coping with chronic Facial pain and temporomandibular disorders: An epi­ pain? Curr Pain Headache Rep 2009;13:127–132. demiological study of the Northern Finland 1966 Birth 97. Hobara M. Beliefs about appropriate pain behavior: Cohort. Cranio 2000;18:40–46. Cross-cultural and sex differences between Japanese 80. Yunus MB. Gender differences in fibromyalgia and Euro-Americans. Eur J Pain 2005;9:389–393. and other related syndromes. J Gend Specif Med 98. Moore R, Brødsgaard I, Mao TK, Miller ML, Dworkin 2002;5:42–47. SF. Perceived need for local anesthesia in tooth drill- 81. Huang GJ, LeResche L, Critchlow CW, Martin MD, ing among Anglo-Americans, Chinese, and Scandi- Drangsholt MT. Risk factors for diagnostic subgroups navians. Anesth Prog 1998;45:22–28. of painful temporomandibular disorders (TMD). J Dent 99. Gazerani P, Arendt-Nielsen L. The impact of ethnic Res 2002;81:284–288. differences in response to capsaicin-induced trigemi- 82. Macfarlane TV, Blinkhorn AS, Davies RM, Kincey J, nal sensitization. Pain 2005;117:223–229. Worthington HV. Factors associated with health care 100. Ng B, Dimsdale JE, Rollnik JD, Shapiro H. The effect seeking behaviour for orofacial pain in the general of ethnicity on prescriptions for patient-controlled an- population. Community Dent Health 2003;20:20–26. algesia for post-operative pain. Pain 1996;66:9–12. 83. Epker J, Gatchel RJ. Prediction of treatment-seeking 101. Laguna J, Goldstein R, Braun W, Enguídanos S. behavior in acute TMD patients: Practical application Racial and ethnic variation in pain following inpa- in clinical settings. J Orofac Pain 2000;14:303–309. tient palliative care consultations. J Am Geriatr Soc 84. Dao TT, Knight K, Ton-That V. Modulation of myofas- 2014;62:546–552. cial pain by the reproductive hormones: A preliminary 102. Burgess DJ, Nelson DB, Gravely AA, et al. Racial report. J Prosthet Dent 1998;79:663–670. differences in prescription of opioid analgesics for 85. LeResche L, Saunders K, Von Korff MR, Barlow W, chronic non-cancer pain in a national sample of vet- Dworkin SF. Use of exogenous hormones and risk of erans. J Pain 2014;15:447–455. temporomandibular disorder pain. Pain 1997;69:153– 103. Deepmala D, Franz L, Aponte C, Agrawal M, Jiang 160. W. Identification of provider characteristics influencing 86. MacGregor EA. Contraception and headache. Head- prescription of analgesics: A systematic literature re- ache 2013;53:247–276. view. Pain Pract 2013;13:504–513. 87. Meriggiola MC, Nanni M, Bachiocco V, Vodo S, Aloisi 104. Contreras-Huerta LS, Baker KS, Reynolds KJ, Batal- AM. Menopause affects pain depending on pain type ha L, Cunnington R. Racial bias in neural empathic and characteristics. Menopause 2012;19:517–523. responses to pain. PLoS One 2013;8.

29

Anatomy and Neurophysiology ofChapter Orofacial PainTitle X2 Michael Tal, DMD, MS Luis Villanueva, DDS, PhD Marshall Devor, PhD

When it comes to pain, dentists take a bad rap. Going to the dentist universally conjures up fears of painful procedures—the whirring high-speed drill, huge syringes, and blood-curdling extractions. Nothing could be more unfair; dentists are angels of pain relief. A patient who enters a dental clinic with a mind-gouging toothache is almost certain to leave within an hour with the problem resolved and the pain gone. And not only gone, but gone permanently, with very little likelihood of pain re- currence. This happy ending is most unlikely if you visit a rheumatologist with a painful hip or an orthopedist with an aching back. On the other hand, some painful conditions in the trigeminal region are much more diffi cult to treat than dental caries. Consideration of the anatomy and physiology of craniofacial innervation, compared with innervation at spinal levels, can provide useful insights into what works, what does not work, and why.

Pain in the Orofacial and Cranial Region

All tissues of the body receive sensory innervation, with the sole exception of the brain parenchyma. Although the fundamental patterns of innervation and information processing are similar throughout the body, the orofacial and cranial region has certain peculiarities that motivate a special focus on this region with respect to pain. Most strikingly, the head is functionally unique, mounted as it is on a narrow stalk (the neck), subject to continuous accelerations in all three planes, and containing the vestibule to the digestive system and the lungs, the special sensory organs, and, most important, the brain. The head is also subject to a variety of chronic pain syndromes that do not have obvi- ous parallels in other parts of the body—migraine and trigeminal neuralgia, for example. It is by no means clear why these conditions do not occur in spinal structures. In this chapter, the anatomy and physiology of the pain system that serves the orofacial and cranial region are reviewed, and the features that set this region apart from other somatic tissues are considered.

31 2 Anatomy and Neurophysiology of Orofacial Pain

tors to tactile stimuli is much smaller than to Nociceptive (Normal), heat. Afferent nociceptors in inflamed skin do not generally respond to light brushing of ten- Inflammatory, and der skin, even though this brushing is painful.3,4 Neuropathic Pain Tactile allodynia in the skin has another cause (discussed later). Basic types of pain A third type of pain, neuropathic pain, re- sults from injury or disease of nerves or cen- Normally, pain is felt when signals originating tral nervous system (CNS) structures. This type in thinly myelinated (Aδ) and/or unmyelinated of pain resembles tissue inflammation in the (C) nociceptive afferents reach the conscious sense that spontaneous pain and hypersen- brain. The purpose of pain is protective; exam- sibility are usually present. However, it differs ples include burning your tongue or biting your from inflammatory pain as the injury/disease is lip. The sensation felt (pain) matches the stimu- in neural tissue. This distinction is not without lus (noxious). This is nociceptive pain. problems. Pain due to inflammation in a major Minor tissue injuries, burns, abrasions, nerve trunk (neuritis) is generally considered and infections often cause ongoing pain and neuropathic.5 On the other hand, all peripheral tenderness (hypersensibility). This is inflam- tissues are innervated, so minor trauma to skin, matory pain. Current pain nomenclature di- muscles, or joints also injures nerve fibers, or at vides tenderness into two aspects. First, pain least changes their local chemical milieu. And in response to a normally painless stimulus is yet it would be odd to list painful skin abrasions called allodynia. In allodynia, the sensation felt or infections as examples of neuropathic pain. in the inflamed tissue (pain) no longer matches Nomenclature aside, from the point of view of the stimulus (non-noxious). Second, excessive mechanism, there is considerable overlap be- pain in response to a stimulus expected to be tween neuropathic and inflammatory pain pro- painful is called hyperalgesia.1 Classically, the cesses. Indeed, at segmental levels, and even allodynia and hyperalgesia caused by every- more so in the craniofacial area, it is often not day injuries have been explained by a putative known if a particular chronic pain diagnosis is increase in the responsiveness of nociceptor nociceptive, inflammatory, or neuropathic. endings (peripheral sensitization) resulting from Nociceptive pain and inflammatory pain are chemical inflammatory mediators released in adaptive design features of the nervous system. the injured tissue. The resulting sensitized no- They constitute an alarm bell. Temporary hyper- ciceptors respond at a substantially reduced responsiveness to stimuli in inflammatory pain threshold, to lukewarm water, for example, re- provides a warning and protects against further sulting in heat allodynia (ie, pain in response to damage by reducing use of the body part and a normally nonpainful warm stimulus). Some C by suppressing activity in general. Neuropathic fibers do not respond to any applied stimulus pain, in contrast, reflects abnormal (pathophys- under normal conditions but begin to respond iologic) functioning of a damaged pain system. during inflammation. These are called silent or This type of pain is maladaptive, the equivalent sleeping nociceptors.2 of a defective alarm system that produces false Peripheral sensitization may well account alarms. for thermal allodynia. Evidence is also good that sensitization of normal and silent noci- ceptors to mechanical forces contributes to Tactile allodynia and central sensitization pain on movement and bearing weight in joints Strong evidence suggests that tenderness to and other deep tissues where significant me- the touch (tactile allodynia) after inflammation chanical forces are brought to bear. However, and frank nerve injury results from abnormal it has become increasingly clear that this is not signal amplification in the CNS rather than from the correct explanation for tactile allodynia in sensitized nociceptors. The process is called which a light touch to irritated, tender skin and central sensitization, and it results from a vari- mucous membranes is felt as painful. The re- ety of injury-evoked pathophysiologic changes duction in the response threshold of nocicep- (see following section on neuropathic pain). In

32 Sensory and Motor Innervation of Craniofacial Structures the presence of central sensitization, peripheral for the back of the scalp, which is innervated input entering the CNS along non-nociceptive, by sensory cells in the upper cervical DRGs. thickly myelinated, Aβ touch afferents evokes The bodies of sensory cells have a distinctive pain.6–8 Because mechanical rather than ther- pseudounipolar structure unlike any other cell in mal hypersensibility is the most common the nervous system. With rare exceptions (no- cause of suffering and disability in patients with tably MesV, the mesencephalic nucleus of the chronic pain, pain signaled by Aβ afferents is trigeminal nerve; discussed later), the sensory as important as pain signaled by nociceptors. ganglia are located in a bony cavern between The concept of Aβ pain constitutes a revolution adjacent vertebrae or at the base of the skull in the understanding of inflammatory and neu- and have two axonal processes. One travels ropathic pain. from the cell body through a peripheral nerve, usually containing motor and sensory axons, and terminates in one or more sensory end- The paradox of neuropathic pain ings in innervated tissue. The other runs from Neuropathic pain in the craniofacial area, as the cell body, through the dorsal root or crani- elsewhere, is a significant problem for theoreti- al nerve root, and ends in a cluster of synaptic cal understanding and clinical management be- terminals within the CNS. In the trigeminal sys- cause it is fundamentally paradoxical. Just as tem, the primary sensory neurons reside in the cutting a telephone wire leaves the line dead, trigeminal root ganglion (TRG) and terminate as cutting axons should deaden sensation. Sure presynaptic terminals on postsynaptic neurons enough, complete denervation of a body part of the brainstem trigeminal complex (Fig 2-1). does result in numbness, the hallmark neg- Sensory neurons also reside in parasympa- ative symptom of neuropathy. Yet nerve trau- thetic and enteric ganglia.10 These ganglia are ma and disease are also frequently associated cell clusters intrinsic to certain tissues, nota- with positive symptoms and signs, some that bly the alimentary canal, and can be thought resemble inflammation and others that are of as evolutionary remnants of a primitive, dis- unique. These include (1) spontaneous par- tributed nervous system. They are capable of esthesias (eg, pins-and-needles sensation), carrying out fairly complex functions, such as dysesthesias (unpleasant paresthesias), and peristalsis, independent of the brain. A per- frank pain; (2) allodynic and hyperalgesic re- son’s conscious sensory experience of the gut sponses to stimuli in the partially denervated and other visceral organs is not due to this au- regions; (3) pain evoked by deep palpation and tonomic circuitry but rather to pseudounipolar by movement of the neck or jaw; and (4) electric neurons of the DRGs and cranial nerve ganglia. shock–like paroxysms and hyperpathia. These Signals that originate in sensory neurons res- pathophysiologic pain states are discussed in ident in the parasympathetic or enteric gan- the sections that follow. glia are unlikely to induce sensory percepts. However, there is tentative evidence that such signals may bypass the spinal cord and reach consciousness via the vagus nerve and brain- Sensory and Motor stem.11 Parasympathetic ganglia reside in, and serve, some craniofacial structures, but there Innervation of are no enteric ganglia in the head. The most Craniofacial Structures rostral ones are in the myenteric plexus of the upper esophagus. Sensory neurons Somatovisceral sensation is due to innervation Peculiarities of craniofacial by primary sensory neurons (primary afferents). These neurons reside in the dorsal root ganglia sensory innervation (DRGs) for spinal structures and in the trigem- Primary afferent neurons of the trigeminal (and inal ganglia (with a minor contribution of oth- other cranial nerve) ganglia have several ana- er cranial nerve ganglia) for the head, except tomical and functional features that distinguish

33 2 Anatomy and Neurophysiology of Orofacial Pain

Trigeminal ganglion C fibers V1

V2 Pr5

V3 Sp5O Aδ fibers

Sp5I

Sp5C

Fig 2-1 The trigeminal nerve, its sensory ganglion (the TRG), and trigeminal root ter- minations within the brainstem trigeminal complex. The territory of distribution of the trigeminal nerve divisions—V1 (ophthalmic), V2 (maxillary), and V3 (mandibular)—are shown on the left. Note that sensory neurons of the facial nerve (VII), glossopharyn- geal nerve (IX), and vagus nerve (X) ganglia also innervate craniofacial structures, as do the spinal C1 and C2 DRGs. The divisions of the brainstem trigeminal complex, from caudal to rostral, are Sp5C (nucleus caudalis), SP5I (nucleus interpolaris), SP5O (nucleus oralis), and Pr5 (nucleus principalis). (Drawing modified with permission from Villanueva and Noseda.9)

them from neurons of the spinal DRGs, although level.14,15 This yields a higher mean conduction the functional significance of these differences velocity for trigeminal versus spinal nociceptive is not necessarily obvious. These include fiber signaling, which is in any event faster because types, teeth, trigeminal mesencephalic nucleus, of the shorter propagation distances in the and embryonic origin, which are discussed in head. The reasons for this emphasis on speed the following sections. are not clear. Hoffmann and Matthews16 reported that pe- ripheral nerves in the head also contain fewer Fiber types sympathetic efferent axons than somatic pe- The ratio of myelinated (A) to unmyelinated (C) ripheral nerves and argued that this may be re- afferent fibers in trigeminal nerve tributaries lated to the relative infrequency of sympathet- is higher than in spinal nerves. Cranial nerves ically maintained pain states in the trigeminal have relatively few C fibers.12,13 Related to this, region. The hallmark of sympathetically main- many of the thermoreceptors that innervate tained pain is pain relief after sympathetic block the orofacial area have thinly myelinated Aδ fi- or sympatholysis. Interestingly, trigeminal cuta- bers, whereas in other parts of the body most neous and intracerebral blood vessels receive thermoreceptors are C fibers. The tooth pulp both parasympathetic and sympathetic inner- chamber is also known to have a high propor- vation.17–19 At segmental levels, parasympathet- tion of A-fiber nociceptors compared with the ic innervation of blood vessels is uncommon, if more frequent C-fiber nociceptors at the spinal it exists at all.

34 Sensory and Motor Innervation of Craniofacial Structures

Enamel CartilagEnamele Cartilage

Subchondral Subchondral Dentin Dentin bone bone Gingiva PeriosteumGingiva Periosteum

Periodontal Periodontal Periosteum Periosteum ligament ligament Dental Bone Dental Bone pulp marrow pulp marrow Tooth Tooth Hip joint Hip joint

Fig 2-2 The structural analogy between teeth (left) and epiphysial bone ends (right) may provide useful insights into pain mechanisms in calcified tissues in general. As illustrated in this schematic diagram, tooth enamel is analogous to articular hyaline cartilage (note that neither is innervated), dentin is analogous to subchondral bone, dental pulp is analogous to bone marrow, and the external soft tissues of the tooth (gingiva) are analogous to synovial soft tissue and periosteum of the joint. Important differences are also found between tooth and bone innervation.

Teeth afferents of MesV neurons travel in the motor rather than the sensory root of the trigeminal The teeth are unique structures that have nerve. The functional significance of this anom- no homologue at spinal levels. A tooth is an aly is unclear, although there is a hint of special open-ended, vital, innervated, calcified box neural processing in the fact that, unlike DRGs (dentin and cementum) with an internal cham- and normal cranial nerve ganglia, MesV neu- ber filled with soft neural tissue (tooth pulp rons receive synaptic input. Another hint is that chamber) and coated orally with a relative- although opposing extensor and flexor muscle ly nonvital hard tissue that is not innervated blocks are roughly equal in size at spinal levels, (enamel). Teeth have a clear resemblance to the in the orofacial motor system there is asymme- ends of skeletal long bones with the noninner- try. The jaw-closing muscles, the flexors, are vated (synovial) cartilage being analogous to massive and powerful and have rich muscle dental enamel (Fig 2-2). spindle and Golgi tendon organ innervation. The jaw-opening muscles, the extensors, are small and delicate and lack muscle spindles Trigeminal mesencephalic nucleus and Golgi tendon organs.20 The trigeminal mesencephalic nucleus (MesV), located at the mesopontine junction, is a unique sensory structure that contains cell Embryonic origin bodies of primary afferent proprioceptors, Ia af- The TRG, the largest of the cranial nerve gan- ferents that innervate the jaw-closing muscles glia, is in essence constructed by fusion of (masseter, temporalis, and medial pterygoid) three ganglia associated with the ophthalmic, and the periodontium. In essence, the MesV maxillary, and mandibular branches of the tri- is a cranial nerve ganglion displaced into the geminal complex. All DRG neurons at spinal brain, the only example of this architecture in levels originate in the embryonic neural crest. the CNS. The axons of muscle and periodontal The TRG, in contrast, contains many neurons of

35 2 Anatomy and Neurophysiology of Orofacial Pain

V1 V1 C2 C2 V3 SpSC C V2 Cu B V1 C2,3 C2,3

V2 V2 C3 C3

V3 V3 C2,3 C2,3 C4 C4

Nucleus Nucleus caudalis caudalis

Fig 2-3 Craniofacial input to the brainstem trigeminal complex forms a continuous somatotopic map. Over much of its length, the map follows a segmental pattern with the ophthalmic division (V1) represented laterally (ventral) and the mandibular division (V3) medially (dorsally, left, including inset). Within the nucleus caudalis, the map follows an onion-bulb pattern with the nose and lips represented rostrally and the forehead, jaw, and scalp caudally (right).

ectodermal (placodal) origin as well as neurons minor contribution from the facial nerve (VII). of neural crest origin.21 The back of the scalp, the angle of the mandi- ble, and parts of the ear and throat are innervat- ed primarily by dorsal roots of the C1 and C2 Innervation of the head spinal segments (Fig 2-3). With the exception of Overview MesV, the relevant primary sensory neurons are all located in the corresponding cranial nerve The cranial nerves that support pain sensation ganglia or DRGs. The special senses (smell, are mixed nerves, which means they also con- vision, taste, hearing) and the vestibular sense tain somatic and autonomic motor axons. This are served by cranial nerves I, II, VII, and VIII. should not matter much as, normally, axons The trigeminal nerve (V) is by far the most im- that share a nerve trunk are functionally inde- portant cranial nerve for pain. pendent. However, in the event of nerve inju- ry, adjacent axons may interact, and this could Voluntary motor innervation (including contribute to pain pathophysiology. Interac- somatic and branchial divisions). External tions can be electrical (ephaptic) or chemically ocular muscles are innervated by the oculomo- mediated. A suspected example of the latter is tor (III), trochlear (IV), and abducens (VI) nerves. sympathetically maintained pain (see the sec- The facial muscles of expression are innervated tion titled “Cellular mechanisms” on page 64). by the facial nerve (VII). The muscles of masti- cation are served mostly by the motor branch Somatic and visceral sensory innervation. of the trigeminal nerve (Vm). The muscles that Somatic and visceral sensory innervation of control swallowing and the larynx are served the orofacial region is provided mainly by the by the glossopharyngeal (IX) and the vagus (X) trigeminal nerve (cranial nerve V); partly by the nerves. The spinal accessory nerve (XI) inner- glossopharyngeal nerve (IX), vagus nerve (X), vates certain muscles of the neck and shoul- and spinal accessory nerve (XI); and by a very der, the hypoglossal nerve (XII) supplies motor

36 Sensory and Motor Innervation of Craniofacial Structures innervation to the muscles of the tongue (other though merged within a single perineural/dural than the palatoglossus CN X), and the C1 and capsule, the three divisions of this fused gangli- C2 ventral roots supply muscles underlying the on are preserved; cells of V1, V2, and V3 do not scalp. intermingle much in the TRG. The topographic layout of the TRG is largely preserved as axons Autonomic innervation. Autonomic inner- leave the ganglion and pass into the trigeminal vation is all motor and in the trigeminal region root on their way to the brain. This permits a includes both sympathetic and parasympathet- neurosurgeon to target trigeminal pain sources ic components. Sensory fibers that follow pe- regionally by selectively lesioning parts of the ripheral autonomic pathways, which often carry TRG or selectively sectioning fibers in the tri- visceral sensory information, are not part of the geminal root (see chapter 13). Trigeminal motor autonomic nervous system. The entire sympa- fibers originate in pontine trigeminal motor nu- thetic supply to smooth muscles and glands of clei. They exit the brain as a coherent bundle in the head above the neck, including cranial vas- the trigeminal root, bypass the TRG, and then culature, is from motor neurons of the superior follow mandibular nerve (V3) tributaries into the cervical sympathetic ganglion. These are driv- masseter, temporalis, pterygoid, and digastric en, in turn, by preganglionic sympathetic neu- (anterior belly) muscles and into some small rons of the upper part of the spinal intermedi- muscles in the soft palate and middle ear. olateral column. The parasympathetic ganglia, including the ciliary, pterygopalatine, subman- Ophthalmic division. The ophthalmic division dibular, and otic ganglia, are located within or (V1) is the smallest of the three trigeminal nerve near the cranial structures that they innervate tributaries. After entering the orbit through the (juxtamural), and they are driven by pregangli- superior orbital fissure, the ophthalmic nerve onic motor neurons that reside in the brainstem splits into the frontal, nasociliary, and lacrimal parasympathetic motor nuclei. The axons of the nerves. These supply the upper eyelid, fore- preganglionic motor neurons reach their target head, and scalp; the sphenoid, ethmoid, and juxtamural ganglia via the oculomotor (III), facial nasal sinus cavities; the orbital contents; and (VII), glossopharyngeal (IX), and vagus (X) crani- the upper part of the nose (see Fig 2-1). al nerves. The motor neurons of the parasym- pathetic ganglia in turn have short axons that Maxillary division. The maxillary division (V2) innervate nearby smooth muscle and glands exits the cranium through the foramen rotun- in the trigeminal distribution, including blood dum and enters the pterygopalatine fossa. vessels.17,19 Preganglonic secretomotor fibers that exit the brain in the facial nerve (VII) join V2 en route to the parasympathetic sphenopalatine gan- The trigeminal nerve glion (also known as the pterygopalatine gan- The trigeminal nerve (V) is the largest of the glion). This large ganglion is an important tar- cranial nerves, named because it branches into get for pain control, not so much because of three major peripheral divisions: the ophthalmic its autonomic role but because of its location. (V1), the maxillary (V2), and the mandibular (V3) Sphenopalatine ganglion blocks also block the nerves. These map the face from forehead to adjacent maxillary nerve trunk, and it is for this jaw (see Figs 2-1 and 2-3). All three divisions reason that they provide at least temporary contribute sensory fibers to the meninges and relief in sphenopalatine neuralgia, certain per- the intracranial blood vessels and venous si- sistent headaches, herpes zoster pain of the nuses via a small nerve branch (equivalent to face, and some painful traumatic trigeminal the spinal dorsal ramus) that leaves the nerve neuropathies.22,23 The maxillary nerve provides just distal to the TRG. The brain parenchyma, innervation of facial bones and then continues including the retina, does not receive any noci- anteriorly, exiting the skull via the infraorbital ceptive innervation. foramen to enter the orbit through the inferior Except for MesV, the primary sensory neu- orbital fissure. At this point it is called the infra- rons of all three divisions reside in the TRG, also orbital nerve. This nerve provides postganglion- termed the Gasserian or semilunar ganglion. Al- ic parasympathetic innervation to the lacrimal

37 2 Anatomy and Neurophysiology of Orofacial Pain

and salivary glands and to the mucosal glands nociceptors. Researchers have established that of the maxilla (the hard and soft palate, gingiva, many cutaneous C fibers in the limbs respond maxillary sinuses). The nerve also provides sen- to light touch. Such C-tactile afferents also oc- sory innervation to the teeth of the maxilla and cur in the trigeminal system. A role in pleasant the skin of the middle part of the face, including touch (eg, kiss) sensation has been proposed.24 the lower part of the nose (see Fig 2-1). Among the C nociceptors, a substantial fraction are silent and cannot be activated by any natu- Mandibular division. The mandibular divi- ral stimulus except when they are sensitized by sion (V3) is the largest of the trigeminal nerves inflammation. Many nonhuman mammals have and the only one that carries voluntary motor giant motile facial hairs, that is, vibrissae, with fibers. This nerve exits the cranium through the follicles richly innervated by nociceptors and foramen ovale and divides into four tributaries low-threshold Aβ afferents that are sensitive to in the infratemporal fossa: the auriculotempo- the direction and dynamics of vibrissal bend- ral, inferior alveolar, lingual, and buccal nerves. ing. The vibrissae are actively whisked back The auriculotemporal nerve provides sensory and forth and, like fingertips, provide the animal innervation to the skin of the temporal region, with essential detailed touch information. including the ear lobe, and to the temporoman- dibular joint (TMJ). It also carries postgangli- onic parasympathetic motor axons from the Nasal and oral cavities otic ganglion that serve the parotid gland. The The surface of the nasal and oral cavities, in- inferior alveolar nerve enters the mandibular cluding the cranial air sinuses, is covered with a canal and supplies the teeth of the mandible. mucus-secreting epithelial membrane. A special Its mental nerve branch emerges through the keratinized mucosa covers the dorsal surface of mental foramen to supply the skin of the cheek, the tongue. This tissue is served by the same the mucous membrane of the lower lip, and the families of trigeminal primary afferent neurons vestibular gingiva of the mandibular teeth from that serve the skin, including a rich contribution the foramen anteriorly to the midline. The lin- by C polymodal nociceptors. However, the lack gual nerve innervates the anterior two-thirds of of the tough, poorly penetrable, external cori- the tongue, the floor of the oral cavity, and the um layer of skin provides mechanical, chemical, lingual periodontium. The buccal nerve (also and thermal stimuli with much easier access to called the long buccal to distinguish it from the sensory receptor endings in mucosal tissues. It motor buccal branch of VII) innervates the mu- also permits enhanced access to drugs, such cous membrane, the vestibular gingiva, and the as local anesthetics, and allows a route of de- gingiva posterior to the mental foramen. The livery of drugs to capillary beds and the circu- chorda tympani nerve, a branch of the facial latory system. The oral cavity is richly invested nerve (VII), joins the lingual nerve in the infra- with receptors for touch and cold sensation, but temporal fossa, carrying taste fibers from the many areas have little sensitivity to heat. This is anterior two-thirds of the tongue as well as the why the anterior part of the hard palate is prone parasympathetic supply to the submandibular to burns; there is only minimal feeling there and sublingual salivary glands (see Fig 2-1). that food items are too hot.25 Ongoing pain in conditions such as burning mouth syndrome is very likely due to abnormal activity of intraoral Pain and specific craniofacial structures thermal afferents. Inflammation is not obvious Skin in burning mouth syndrome. This has led to the hypothesis that the abnormal neural activity un- The skin of the face and scalp, including its derlying this type of pain may be neuropathic in innervation, is fundamentally the same as the origin (see chapter 12). skin in other parts of the body. It is served by a variety of thickly myelinated low-threshold Nasal cavity and smell. The olfactory epithe- mechanoreceptive afferents (Aβ fibers); thinly lium on the upper nasal turbinate bones has the myelinated afferents, including Aδ nociceptors; same trigeminal innervation as all other nasal and unmyelinated C fibers, many of which are and oral mucosas. The intense burning sensa-

38 Sensory and Motor Innervation of Craniofacial Structures tion that follows sniffing of irritating substanc- as it is to taste buds on the tongue. The taste es, such as ammonia or spicy horseradish, is of piquant food items, such as garlic and hot thought to be due to the activation of trigeminal peppers (capsaicin), is due to neither taste nor C-fiber chemonociceptors, not olfactory recep- olfactory receptors but to activation of trigem- tors. The situation is similar for the sneezing re- inal chemonociceptor endings in the tongue, flex. Trigeminal chemonociception must be dis- palate, gingiva, and nasal cavity that carry cor- tinguished from olfactory chemosensation. The responding sensory transduction molecules latter is based on an entirely different physiol- (eg, TRPA1, TRPV1). Trigeminal innervation is ogy and functional architecture and a different likewise responsible for all other (nonchemical) cranial nerve, the olfactory nerve (I) (and in non- somatosensory discrimination in the oral cav- human mammals also the vomeronasal nerve). ity, such as heat, cold, and pinprick. Finally, The sensory cell bodies of trigeminal chemo­ low-threshold mechanoreceptors (LTMs) of the nociceptors are located in the TRG. Their axons oral mucosa and tongue, together with peri- enter the CNS in the pons and terminate in the odontal and jaw muscle proprioceptors, pro- brainstem trigeminal complex. Olfactory che- vide a sense of the texture of food. These var- moreceptor neurons do not reside in a ganglion ious sources of sensory input, taste, olfaction, but rather within the nasal olfactory epithelium oral mechanosensation, and proprioception are itself. They are ciliated bipolar neurons with integrated in the cerebral cortex to provide the axons that enter the brain along the olfactory final complex sensory experience that people nerve (I) to synapse in the olfactory bulbs. associate with eating a fine meal. Interestingly, there are occasional reports Oral cavity and the tongue, taste, and fla- in which food items, not painful in themselves, vor. The same distinction must be made be- are reported to trigger pain. The most common tween chemonociception in the oral cavity and example is migraine, which is said to be some- the sense of taste. Taste chemoreceptors are times triggered by eating yellow cheese and specialized nonneural transduction cells that chocolate or by drinking coffee or red wine. are present in the taste buds of the tongue Whether this is due to the taste/smell of these and pharynx. The taste receptor cells activate foods or to some chemical absorbed into the axonal endings of myelinated visceral primary circulation is not clear. Headache can also be afferents of the chorda tympani nerve, whose triggered by drinking orange juice or by eating cell bodies reside in the geniculate ganglion of pineapple, pickled onions, or food items that the facial nerve (VII). They do not belong to the contain monosodium glutamate, tyramine, or trigeminal nerve (V) and are not thought to be sucrose (see chapter 10). Various gustatory associated with pain in the oral cavity. An in- stimuli to the tongue, such as sweet, can in- teresting example is the tingling, almost pain- duce sweating in the trigeminal nerve distribu- ful sensation in the back of the throat caused tion. In some patients, taste and smell induce by drinking carbonated fizzy drinks. This sen- paroxysmal pain attacks resembling trigemi- sation is due to the response of trigeminal nal neuralgia.27–29 The triggering mechanism is acid-sensing chemonociceptors (V) activated unknown. by carbonic acid in the drink, while the flavor of the drink is sensed by taste buds (VII).26 Pharynx and larynx. As noted, the lack of the Tastants are molecules that activate taste cornified outer layer of skin in the oral mucosa chemoreceptors and give rise to the five ba- permits easy access of stimulants (mechani- sic taste modalities: sweet, sour, salty, bitter, cal, thermal, and chemical) to mucosal sensory and umami (the taste of monosodium gluta- receptor endings and easy access of applied mate). Olfactants are the much larger family drugs to the underlying vasculature. However, of molecules that activate olfactory receptor this poses special problems in preventing viral neurons and give rise to a sensation of smell. and bacterial infection via the nasal and oral Olfactants can access the olfactory epithelium cavities. Protective enzymes are present in the via the nostrils and the oral cavity via the phar- saliva to help manage this problem. Nonethe- ynx. The flavor of food is due at least as much less, infection, irritation, and consequent pain- to olfactory stimulation via these two routes ful inflammation in this area are common.

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