Guide to the Neurobiology of Dental Analgesics

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i GUIDE TO THE NEUROBIOLOGY OF DENTAL ANALGESICS AMANDA LEBOFSKY A Thesis Submitted to the Division of Natural Sciences New College of Florida in partial fulfillment of the requirements for the degree Bachelor of Arts in Biology Under the sponsorship of Dr. Alfred Beulig Sarasota, Florida May, 2009

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ii Acknowledgements Foremost I would like to thank Christin e Hamilton-Hall DMD, MD, and her staff, Kavitha, Donna, and Cathy. Also, I would lik e to thank Denis Trupkin DDS, and George Babyak DDS, for providing me with comfortabl e pediatric dental care and sparking my interest in dentistry at a very young age. Additional gratitude is warranted to my a dvisor, Dr. Alfred Beulig, for guiding me though my time at New College and helping me succeed at putting together this senior thesis. Also, the committee members, Dr. Amy Clore and Dr. David Mullins. Dr. Clore, your love of the cytoskeleton and interpretiv e dances of filament movements will never be forgotten. On a more personal note, after 22 years of lif e on this Earth I have collected a group of friends and family members who mean so much to me, the words are practically synonymous. First off, I would like to th ank my father, Scott Lebofsky. A more supportive, loving father does not exist. My sister Dana, I look forward to attending your college graduation a decade from now. My gr andparents, Richard Lattimore and Patricia Goldstein, for supporting my education. Jane, for remaining a positive female influence in my life and cooking me dinner whenever I return to Fort Lauderdale. The Edmondson clan, for helping me keep my sanity in high school and remaining with me throughout my time at New College. My time spent in your hou sehold greatly paid off when I left home and had to wash my own dishes. A special thank you is deserved to all my besties. Alyssa, you have remained a good friend for many years and I hope our bonds are never broken. To the Poon Squad, Camila, Alana and Laura, for cheering me thro ugh the thesis process and brightening my life in more ways than you know. Backpack inging through Mesoamerica with the Squad was a memorable adventure and I wish you all luck writing your own senior pain-in-thetush, I mean thesis. Madi, Lizzy, Erica, Cat, Carli and Jenna, some of the most wonderful people that I have come to love. Living with all of you has shaped my life in a very positive way and Im glad our paths crossed at New College. This thesis is dedicated to the memory of my Nanny and Poppy, Helene and Allan Lebofsky. Above all others, they are th e motivating force behind my work.

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iii List of Figures Figure 1: Model of the Gate Control Theory Figure 2: Illustration of the innerv ations of the Trigeminal Nerve Figure 3: Graphic interpretation and cross sec tion of the fifth brainstem nuclear complex (VBSNC) Figure 4: Flow table of the biopsychsocial model of pain evaluation *All figures found in the A ppendix starting on page 66

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iv GUIDE TO THE NEUROBIOLOGY OF DENTAL ANALGESICS Amanda Lebofsky New College of Florida, 2009 ABSTRACT This thesis serves as a comprehensive analysis of the scientific communitys understanding of the neurobiology of pain tran smission in the orofaci al region thus far into the 21st century. Investigation of nocicep tive transmission and brain relay mechanisms of the trigeminal brainstem nuclear complex (VBSNC) are expanded upon to provide insights of how the body processes and modulates sensory information in the mouth. Another main focus is placed on the way in which western medicine conducts the assessment and management of pain. This incl udes a description of various pain models, holistic treatments, and clinical measur es used to mask pain transmission. Orofacial disorders linked to chronic or persistent pain, including burning mouth syndrome and trigeminal neuralgia, are prev alent in the United States yet modern medicine is only capable of treating the disorder rather than determining causation. Contents also include an analysis of modern dental analgesics, specifically their uses, pharmacokinetic properties and physiological mechanisms. Recommendations are

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v provided as to new approaches in research aimed to explore the future of pain management according to notable pain researcher Ronald Melzack. Dr. Alfred Beulig Division of Natural Sciences

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vi Table of Contents Page Acknowledgements List of Figures ii iii Abstract iv 1. Introduction 1 History of Pain Theory 1 Complexity 5 Pain Related to Dentistry 7 2. Chapter 1: Pain [An Overview] 10 Neurobiology 10 Assessment 13 Adults Children Treatment 16 Clinical Holistic 3. Chapter 2: Orofacial Pain [an Overview] 23 Trigeminal Nerve Anatomy 23 Trigeminal Brainstem Nuclear Complex Mechanisms 25 Importance of Subnucleus Caudalis Thalamic and Cortical Neural Mechanisms Reflex and Behavioral Mechanisms Disorders 31 Dental Pain

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vii Trigeminal Neuralgia/Pre-Trigeminal Neuralgia Burning Mouth Syndrome Temporomandibular Disorders Biopsychosocial Model 37 4. Chapter 3: Dental Analgesics 40 Inhalation Anesthesia 41 Intravenous Sedation 43 Local Anesthesia 45 Classification Pharmacokinetics Additives Elimination Complications Alternative Methods 53 Acupuncture Computerized Delivery 5. Conclusion and Recommendations 55 Gaps Discovered 55 Future Initiatives 58 Bibliography 60 Picture Appendix 66 Glossary 70

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1 Introduction Painone recognizes it im mediately. It may be masked as the fiery sensation of a burn moments after a finger touches the stove or as a dull ache above the brow after a long day of stress. Despite its causes, the se nsation is pain. In be nign form, it warns one that something is not quite right and action should be taken by swallowing medication or seeing a doctor. At its worst, pain may rob an individual of produc tivity, well being, and, for the many suffering from chronic pain ones very quality of life. Pain is a complex sensation that differs enormously among individua ls, even those with id entical injuries or illnesses. Today, pain is recognized as a unive rsal disorder and a costly public health issue. History of Pain Theory Ancient civilizations recorded on ston e tablets accounts of pain. All early treatments consisted of applying pressure, heat, sun, and water. Early humans viewed pain as evil and the product of magic. This mindset led the responsibility of pain treatment to sorcerers, shamans, priests, and priestesses, who utilized herbs, rites, and ceremonies to relieve the individuals suffering (Meldrum, 2003). The Greeks and Romans were the first to advance a theory of sensation, the idea that the brain and nervous system have a role in producing the pe rception of pain. In the days of Aristotle, pain was viewed as the antithesis of pleasure and was categor ically separated from the other five senses. It was not until the 1400s and 1500s that society supported these All italicized terms are defined in the glossary starting on page 70

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2 theories. During this time, Leonardo da Vinci and his contemporaries came to believe the brain was the central organ responsible for se nsation and that the spinal cord transmits sensations to the brain (Vertosick, 2000). The study of the body and the senses was ma intained as a subject of wonder for the world's philosophers well into the 19th century. In 1664, the Fr ench philosopher Rene Descartes described the first "pain pathway." His theory was based on the idea that pain is produced by a direct transmission system fr om injured tissues in the body to a pain center in the brain. In one of his more fam ous works, Descartes tried to explain how particles of fire travel to the brain when in contact with the body (Procacci and Maresca, 1994). In 1840, Johannes Muller presented a theory on the specific energies of nerves In accordance with the traditional doctrine of the senses, Muller posited five kinds of sensory nerves. In his theory, th e fifth class (the nerves of feeling) was responsible for a number of different sensations: tickle, itch, shudder, pleasure, pain, fatigue, suffocation, warmth, cold, touch, and movement. He be lieved nerve specificities were based on differences in their mode of arousal and in th e state of the organism at the time of arousal. Mullers work is important because his doctrin e of nerve-specificity effectively trumped the straightforward theories put forth by Descar tes. He demonstrated that different objects produce the same effect via the same nerves, and the same object produces very different effects with different nerves (Vertosick, 2000). Up until the 20th century, despite theoretical adva nces, there was still an issue with pain therapy. Even in the 1950s, there was no consideration for the psychological contributions to pain, such as past experience. Instead, pain intensity was viewed as being proportional to the amount of injury or pathol ogy. Back then, patients who complained of

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3 back pain with no identifiable source were sent to psychi atrists. Clinicians saw the problems with Mullers specificity theory and developed several pattern theories, which themselves were labeled vague and in adequate. However, the pattern theories moved the field of pain study away from the periphery and into the spinal cord, setting the stage for the gate control theory, one of the most widely accepted pain theories of today (Meldrum, 2003). In 1965, Pat Wall and Ronald Me lzack published a paper in Science entitled a New Theory of Pain. This paper described the gate control theory, which is illustrated in Figure 1. This theory is based on five propos itions, which are taken directly from Melzacks 1996 publication entitled Gate C ontrol Theory: On the Evolution of Pain Concepts: 1. The transmission of nerve impulses from afferent fibers to spinal cord transmission cell s is modulated by a spinal gating mechanism in the dorsal horn. 2. The spinal gating mechanism is influenced by the relative amount of activity in large diameter and small diameter fibers: activity in large fibers tends to inhibit transmission (close the gate) while small fiber activity tends to facilitate transmission (open the gate). 3. The spinal gating mechanism is influenced by nerve impulses that descend from the brain. 4. A specialized system of large diam eter, rapidly conducting fibers (the central control trigger) activates selective chronic pain processed than

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4 then influence, by way of descending fibers, the modulating properties of the spinal gating mechanism. 5. When the output of the spinal cord transmission cells exceeds a critical level, it activates the action systemt hose neural areas that underlie the complex, sequential patterns of behavi or and which receive signals that represent the characteristics of pain. This theory is unique because it was the fi rst of its kind to empha size the modulation of inputs in the spinal dorsal hor ns and the dynamic role of the brain. Also, this was the first account that recognized psychologica l factors to be an integral part of pain processing. By the mid-1970s the gate control theory was included in almost every major textbook in the biological and medicinal sciences (Dickenson, 2002). Over the years, the gate control theory ha s been slightly retooled to better answer the questions that arose afte r its publication. Findings in paraplegics a nd victims of phantom limb syndrome did not fit into the theory and additional parameters were warranted. This led to the neuromatrix theory of pain, which perceives the body as a unity and identifies the self as a characte ristic distinct from other people and the surrounding world. In this new theory, Melzack proposed that the anatomical substrate of the body-self is a wide spread network of neurons (labeled the neuromatrix) that consists of loops between the thalamus and cortex as well as between the cortex and limbic system (Melzack, 2001). He maintained that the loops diverge to permit parallel processing in different components of the neuromatrix but also c onverge repeatedly, permitting interactions

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5 between the output products of processing. This repeated cyc lic processing and synthesis of nerve impulses through the neuromatri x creates a pattern referred to as the neurosignature The neurosignature of the neuromat rix affects all nerve impulses that flow through it. Subsections of the neuromatri x process specialized information related to major sensory events (such as temperatur e change and injury) and are labeled as neuromodules which create their own impressions of the larger neurosignature. According to the neuromatrix theory, the ne urosignature splits, with some patterns traveling to areas of the brain (dubbed the sentinent neural hub ) in which the stream of nerve impulses converts into a stream of aw areness that is continually changing. The other patterns proceed through neural networks that facilitate movement (Melzack, 2001). The neuromatrix theory of pain is by no means meant to suppl ant the gate control theory. Both theories are widely accepted in the scientific community; the neuromatrix theory merely covers the aspects of pain th at remain unexplained by the theory put forth in 1965. Complexity of Pain As one can tell by the complex theories de scribed above, pain sensation consists of multiple levels that correspond to both the body and mind. Interestingly, the same painful stimulation to one indi vidual may yield a very differe nt degree of sensation in another. Environmental and genetic factors mold an individuals in terpretation of pain. This section is designed to expand upon the genetic, gender, and psychological factors that augment pain perception so that a better understanding of the complexity of pain may be established.

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6 There is no solid boundary or statistic th at can account for the relative importance of genetic versus environmental factors in human pain perception. However, heritability for nociceptive and analgesic sensitivities in mice has been estimated to range from 28% to 76% (Mogil et al., 2003). Only a handful of genes have been identified as being associated with the perception of pain in humans. Single nucleotide polymorphisms (SNPs) are found in genes that code for melanocortin-1 receptors and neuronal cytochrome P4502D6 These SNPs are thought to be associ ated with alterations in opioid analgesia in humans (D iatchenko et al., 2005). A congenital insensitivity to pain has been linked to the gene encoding a subunit of serine palmitoyltransferase and the gene encoding a nerve growth factor-specific tyrosine kinase receptor (Mogil, 1999). Also, a common SNP in codon 158 (val138met) of the gene that codes for Catecholamine-O-methyltransferase (COMT) has been theorized to contribute to genetic differences in pain perception. This particular enzyme is linked to the regulation of catecholamin e and enkephalin levels (Nagasako, 2003). Three haplotypes (low, average, and high pain sensitivity) of the gene encoding COMT have been identified. These haplotypes encompass 96% of the human popula tion and five of their combinations are associated with sensitivity variations to pa in. The low pain sensitivity haplotype produces higher levels of COMT enzymatic activity when compared to the other two. All of this information proves COMT activity substantially influences pain sensitivity, and the three haplotypes determine COMT activity in humans (Diatchenko et al., 2005). With respect to genetics in a much broade r sense, it is now widely believed that pain affects men and women differently. While the sex hormones estrogen and testosterone certainly play a role in this phenom enon, psychology and culture may partly

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7 account for differences in how men and women receive pain signals (Keefe, 2000). In the past 15 years, many scientists have turn ed their attention to the study of gender differences and pain. Their fi ndings suggest that women rec over more quickly from pain, are more likely to seek help, and are less li kely to allow pain to control their lives (Fillingim and Unruh, 2000). In one experiment male mice were injected with estrogen, which appeared to lower their pain threshol d. When the tables were turned and females were injected with testoster one, their experimental pain to lerance elevated (Kim et al., 2004). Another factor associated with the comple xity of pain is the psychological factor. Several volumes and articles have been written about this subj ect but this thesis is more of a biological analysis of pain, and so the psychological dimensions will be briefly examined. As already touched upon, pain is an intricate perceptual experience that is highly influenced by a wide range of psychosocial factors, including emotions, social and environmental context, the individuals personal meaning of pain, and beliefs, attitudes, and expectations, as well as biological factors. Pain (especially when persistent or chronic) has the ability to influence all asp ects of a persons functi oning, be it emotional, interpersonal, or physical (Turk and Okifuji, 2002). The biopsychosocial model, which is further addressed in the second chapter, is a popular tool used by pain therapists. It assesses illness as a dynamic and recipr ocal interaction between biological, psychological, and sociocultural variables (Keefe et al., 2004). The psychology of pain is heavily based on the patients beliefs about th e meaning of symptoms and their ability to control pain and the impact of pain on their life. In general, psychological treatments for

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8 pain are most effective when incorporated with other treatment components (such as pharmaceuticals) (Price, 2000). Pain Related to Dentistry One of the best places to witness the complexity of hu man pain is in the dental office. Often in the waiting room, individuals squirm in their seats and their pupils dilate whenever the sounds of the drill are heard while others calmly read an outdated magazine. This author finds it nearly impossi ble to talk about den tistry without someone mentioning the word pain or insinuating pa inful situations. Indeed, analgesics are a necessary tool for any dentist a nd are considered one of the main topics of focus in dental research. There are even several journa ls dedicated to the subject, including Anesthesia Progress (an official publication of the American Dental Society of Anesthesiology) and The Journal of Orofacial Pain This thesis is meant to explore the scient ific understanding of pain and its relation to dental analgesics in the 21st century. The information pres ented is a collaboration of both primary and secondary sources found th rough various Internet databases (google scholar, web of science, pub med, JADA (Journal of the Amer ican Dental Association), and worldcat. The keywords used when sear ching these websites were pain, orofacial pain, dental anesthesiology, local anesthesia, and temporomandibular disorders .In lieu of the several hundred publications on this subject and the papers emphasis on recent findings, citations are almost exclusively restricted to t hose works published from 2000 until now (2009) and to review references th at cover most of the earlier relevant literature. The chapter topics (pain, orofacial pain, dental analgesics) are ordered to ease

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9 the reader into the main focus behind all the research. This thesis is meant to expose the gaps that remain in the scientific unders tanding of pain today and use the available information to predict the future of pain management in the dental office.

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10 Chapter 1: Pain [An Overview] Pain can be characterized as chronic, acute or persiste nt. In the body, chronic pain appears to serve no useful purpose. It does not act as a protection mechanism because there is no identifiable stimuli that is causing the sensation. It appears that chronic pains only purpose is to cause individual s to be miserable (Mersky, 2007). Persistent pain is seen in clinical conditions and is one of the major reasons why an individual would seek medical attention. It can be subdivide d into two categorie s, nociceptive and neuropathic Nociceptive pains are the result of the direct activation of nociceptors that are found in the skin or soft tissue. This activation is seen as a response to tissue injury from an identifiable source/reason a nd usually arises from inflam mation. Neuropathic pains result from a blunt injury to nerves in the peripheral or central nervous systems (Kandel et al., 2000). Pain is a submodality of somatic sensati on. The International Association for the Study of Pain proposes that pain is an unpleasant sensory and emotional experience associated with actual or potential tissue da mage, or described in terms of such damage (Merskey, 2007). Pain sensations, be it burn ing, aching, stinging, prickling, or soreness, are the most unique and quickly identified of all the sensory modalities (Kendal et al., 2000). This chapter will cover the neurobiology assessment, and treatment methods used/known in the medical community today. In keeping with the topic, a comprehensive evaluation of orofacial pain is included in the second chapter. Neurobiology

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11 Pain research is guided by the neurobio logy of nociception. Ce rtain tissues have specialized sensory receptors, ca lled nociceptors that are ac tivated by noxious insults to peripheral tissues (Kandel et al., 2000). Therefore, an evaluation of nociception provides a primary structure for the analysis of brain activity when there is some type of pain onset (Rainville, 2002). Nociception re fers to the objective presence of, or potential for, tissue damage (Wall and Melzack, 2006). Altho ugh pain is closely li nked to the nervous system, there is a distincti on between pain and the neural mechanisms of nociception. The functional anatomy of pain in humans has been mainly studied with magnetic resonancy imaging (MRI) and positron emission tomography (PET) (Peyron et al., 2000). When trying to isolate what area of the body is being affected by nociceptive transmission, attention is paid to the noc iceptor terminals, which are the peripheral endings of primary sensory neurons whose cell bodies are located in the dorsal root ganglia and trigeminal ganglia. They are activat ed by harmful stimuli to the skin or subcutaneous tissue (Morrison et al., 2008). There are four classes of nociceptors: thermal, mechanical, polymodal, and silent. All of these classes are widely distributed in the skin and deep tissues of th e body. Extreme temperatures (above 45 C (113 F) or below 5 C (41 F)) activate thermal nociceptors Mechanical nociceptors come into activation when an intense pressure is applied to the epidermis. Both of these nociceptors are composed of small diameter, thinly myelinated A fibers that conduct signals at approximately 5-30 m/s. When a stimulus (be it mechanical, chemical, or thermal) passes a certain level on intensity (these levels vary with stimulant), then polymodal nociceptors are activated. These nociceptors consis t of small diameter, nonmyelinated C fibers that

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12 conduct slowly (less than 1.0 m/s) when comp ared to the other nociceptors (Costigan, 2000). These three classes work together in or der to express pain. For example, when one smashes their toe on a doorframe there is an initial sharp pain that is followed by a more prolonged (typically ach ing or burning) second pain. The first pain is a product of information transmission from the A fibers of the thermal nociceptors to the mechanical nociceptors. The second, duller pain is transmitted by the C fibers of polymodal nociceptors. Lastly are the silent nociceptors They are found in the internal organs located in the main cavity of the body ( viscera) but typically are not activated by noxious stimulation. However, for unknown reasons their firing threshold is dr amatically reduced by inflammation and various chemical insults (Kandel et al., 2000). The classical nociceptive projection is the spinothalamocortical route (Rainville, 2002). In this pathway, lamina I neurons directly synapse on neurons in the thalamus that project to the primary somatose nsory cortex. This leads to cutaneous temperature perception (Morrison et al., 2008). In the ra t there has been extensive mapping of the ascending nociceptive pathways originating in the spinal cord. These pathways project to specific areas of the brainstem and then progress further al ong the front end of the body to various brain structures. Recent findings i ndicate that one pathway projects from the dorsal horn of the spinal cord to the dorsocaudal medulla This same pathway then continues on to the ventromedian nucleus of the thalamus, and fi nally to the dorsolateral frontal lobes (Rainville, 2002).

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13 Another ascending pathway projects from the spinal cord to the parabranchial nucleus (Pb), and then continues on to the hypothalamus and the amygdala Additional findings suggest that nociceptive info rmation may be transmitted to the forebrain from the Pb. This pathway is capable of transmitting nociceptive activity from the Pb to the intralaminar thalamus, and from there to the frontal cortices of the brain (Kandel et al., 2000). There is limited information known of th e descending modulation of nociceptive activity. Currently it is believed that the periacqueductal gray (PAG) area has a key role in descending mechanisms that help contro l spinal nociceptive activity. Work in rats, cats, and monkeys, has shown that ther e are critical areas such as the somatosensory areas, the insular cortex and the medial prefrontal cort ex, (including the anterior cingulate cortex (ACC)) to descending nocicetive pa thways (Morrison et al., 2008). Studies show that higher order cerebral structures receive and integrate nociceptive information as a part of regulating behavior These structures are potential sources of descending influence on nociceptive processes. However, the functional significance of these ascending and descending pathways has ye t to be understood in humans (Rainville, 2002). Assessment While the neurology of pain is important so is the clinicians job of pain assessment. All measurement techniques are su bject to biases since there are no direct measurements of pain. This section describe s the pain assessment approaches that are currently used in both adult a nd pediatric patients along with their associated difficulties.

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14 Assessment of Adult Pain Past methods of pain measurement in a dults treated pain as though it were onedimensional. These methods included the use of verbal/numerical scales and visual analog scales. The scale measurement of pain assessment provides simple, efficient, and minimally intrusive results. They have been widely used in research and clinics to obtain a quick index of pain intensity. Verbal assessmen t scales consist of a series of verbal pain descriptors ordered from least to most inte nse (for example: no pain, mild, moderate, or severe). Numerical rating scales consist of numbers 0 to 10 or 1-100, with end point 0 meaning no pain and the highest numbering la beled worst pain possi ble. In each of these scales patients choose which word/number best represents their pain intensity at the moment (Wall and Melzack, 2006). The main disadvantage in all of these scales is the treatment of pain as a unidimensional sensation that can be measur ed with a single scale. Each pain has individual qualities and the variety of the qua lities cannot be categor ized under a single linguistic label of intensity (Morrison et al., 2008). The pain of a broken bone is obviously different from that of a burn, just as the pain of back surgery is uniquely different from the sensation caused by an earache. The year 1971 marked the developmen t of the McGill Pain Questionnaire by Melzack and Torgeson. The Questionnaire consists of 3 major classes of word descriptors (sensory, affective and evaluative) that ar e used by patients to specify their pain experience. It also includes an intensity scale and other items which are used to determine the properties of pain experience. The questionn aire was designed to provide

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15 quantitative measures of clinical pain that can be treated statistically. The 3 major measures are the pain rating index (PRI) (whi ch is based on 2 types of numerical values that can be assigned to each word descript or), the number of words chosen, and the present pain intensity based on a numerical scale from 1 to 5 (Melzack, 1975). It should be noted that Melzack helped design the McGill Pain Questionnaire and then wrote an article 4 years later describing how efficient it is at assessi ng pain. The Questionnaire is still used today but it has received some criticism due to the fact that because the factors measured are so highly correlated, they are no t distinct. According to Turk and peers, only the PRI results of the test ar e of any value (Turk et al., 1985). Behavioral approaches to pain meas urement consist of a wide array of observational techniques and rating scales. Thes e techniques are helpful when the patient is preverbal, or has a poor command of language (Wall and Melzack, 2006). Physiological approaches to pain measurem ent include a measurement of heart rate, blood pressure, electrodermal activity, electromyographic activity, and cortical evoked potentials. These approaches are limited b ecause although there are many physiological, immune and endocrine events that occur when there is the experience of pain, many changes in these systems are general responses to stress and theref ore are not unique to pain (Wall and Melzack, 2006). Assessment of Pediatric Pain When assessing a childs pain, the method being used must take into account the childs age, cognitive level, th e type of pain, and the situat ion in which the pain started. There is no single measure that can be used for all children with all types of pain

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16 (Bulloch and Tenenbein, 2008). Currently it is believed that the most effective method of pain measurement in children is thro ugh self-report (Wall and Melzack, 2006). Verbal/numerical scales and vi sual analong scales are used in pediatrics as well. Recent publications cite that children as young as 3 are capable of giving a reliable self-report on pain intensity with the use of assessment tools (Wall and Melzack, 2006, and Bulloch and Tenenbein, 2008). Different versions of the visual analog scale have been adapted to assess pain in young children over th e age of 3. In this case a visual analog toy (acting as the assessment tool) is implemented and pl aced on a colored analog scale which changes from light pink to deep red with increasing intensity (van Dijk, 2002). Face scales (where faces are used to express vary ing amounts of pain) are classified as a type of colored analog scale. Non-verbal measures can be used in pain assessment involving children. These methods include asking child ren to draw or describe th e color of their pain (Wall and Melzack, 2006). The behavioral measures of pain seen in children are based on vocalization, facial expression and body movement. Be havioral assessment caries the ever-present challenge of distinguishing if behavior is because of pain or motives other than pain (such as hunger or stress). Biological meas ures that are taken into a ccount when assessing pain are heart rate, oxygen saturation of hemoglobin and sweating. Once again, while these measures are helpful to the clinician, they are not specific to pain type or the sensation of pain at all (Wall and Melzack, 2006). To summarize, pain is a complex percepti on and thus its description varies from person to person. Pain assessment is fundamentally the same in both adults and children with a few additional models geared towards preverbal patient cases. The need for some

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17 type of pain assessment has led to the development of various ranking systems and observational techniques. These methods have matured over time as our understanding of pain has become more multidimensional. Treatment Clinical Pain Management Naturally, the treatment of pain follows its assessment. Over-the-counter pain relievers include aceteminophen (Tyl enol, aspirin free Excedrin), nonsteroidal antiinflammatory drugs (NSAIDs) (asprin, Motr in, and Aleve) and topical corticosteroids (Cortizone). Nociceptive pain is usually treated with anti-inflammatory, or analgesic medications, where neuropathic pain is treated with antidepressants, lidoderm patches, or antiepileptic drugs (Maizels and McCarberg, 2005) Acetaminophen and NSAIDs both have highly se lective analgesic effects that result from their inhibitory actions on the synthesis of prostaglandins (PGs). PGs are lipid mediators that are derived from arachidon ic acid. They play essential roles in the pathogenesis of inflammation, fever, and pain (Ar onoff et al., 2006). PGs themselves are not significant mediators of pain. Rather, they increase the sensitivity of nociceptors to other stimuli in the tissue. Th ey are responsible for activati ng silent nociceptors into a state in which they are easily excitable (Steinmeyer, 2005). NSAIDs are the most commonly used drugs worldwide for treating pain, arthritis, cardiovascular diseases, and for colon cancer prevention. However, their side effects include gastrointestinal ulcers and delayed healing (Tarnawski and Jones, 2003). Only NSAIDs can reduce inflammation along with pain and fever. On the other hand, while

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18 acetaminophen is used for pain management it lacks significant anti-inflammatory activity and is a poor inhibitor of platelet function at high doses (Aronoff et al., 2006). Aceteminophen poisoning is surprisingly common. In of 2002, in the UK, 50% of poisoning admissions involved acetaminophen; this figure is 10% in the US (Dargan and Jones, 2002). NSAIDs are also available in prescription strength while acetaminophen is not. Topical pain relievers are also available OTC. These creams, lotions, or sprays are applied to the skin to relieve pain caused by sore muscles and arthritis. They work by binding to nociceptors in the skin and cau sing an initial excitation of the neurons, followed by a period of enhanced sensitivity perceived as itching, prickling, or burning. This is thought to be because of a selective stimulat ion of C fibers. The initial sensation is followed by a refractory period with reduced sensitivity and, after many applications, persistent desensitization (Mason et al., 2004) Examples of topical pain relievers are Aspercreme, Ben-Gay, Icy Hot, and Capzasin-P. Corticosteroids, opioids, lidoderm patches, antidepressants, and anticonvulsants make up the category of prescription pain re lievers. When given by medical professionals to control pain, corticosteroids are generally administered by injecti on or in a pill form. They enter the cell to combine with steroid receptors in the cytoplasm The corticosteroid/receptor combination then ente rs the cells nucleus where it influences gene expression and forms a prot ein that inhibits the enzyme phospholipase A 2 (Kandel et al., 2000). This enzyme regulates cell activities over a wide range of metabolic functions (including in flammation). Corticosteroids also alter a cell membrane s ion

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19 permeability and modify the production of neurohormones (Tarnawski and Jones, 2003). Some examples include Deltasone, Hydeltrasol, and Solu-Medrol. Opioids are narcotic pain medications that contain natural, synthetic, or semisynthetic opiates Opioids are mostly used for acute pain such as short-term relief after surgery, because patients are prone to addict ion if they use opioids for a long amount of time. They are effective against severe pain and do not pose the risk of internal bleeding like other pain medications (Berde and Nur ko, 2008). Opioids work at the level of the central nervous system by specifically activat ing membrane receptors, thus interacting with the complex endogenous neurotransmitter system (Keiffer, 1999). Morphine, fentanyl, oxycodone, and codeine are all opioids. Lidoderm patches are another means of topi cal pain relief that can only be used with a prescription. In these patches, lidoc aine electrically stabilizes the nerves membranes by inhibiting ionic fluxes necessary for the conduction of action potentials. They are used to treat neuropathic pain and ar e applied to intact skin to cover the most painful area. They typically last about 12 hours and up to 3 patches at a time may be applied (Gidal, 2006). Antidepressants and anticonvulsive drugs are prescribed for chronic pain patients that have seen no resolution with other treat ments. Antidepressants can be used to treat pain because they adjust neurotransmitter levels in the brain. Patients with chronic pain may see some relief with antidepressants because they increase the availability of the bodys signals for well-being and relaxation. Tricyclic antidepressants are thought to impact pain transmission in the spin al cord by inhibiting the reuptake of norepinephrine

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20 and serotonin both of which are key components to descending pain pathways (Maizels and McCarberg, 2005). Some examples of antid epressants used in pain management are Cymbalta, Norpramin, and Pamelot. Antic onvulsive drugs are also thought to act at several sites that may be relevant to pain, but the mechanism of th eir analgesic effects remains unknown. As of 2005, they were t hought to limit neuronal excitation and enhance inhibition. Examples include Lamictal and Dilantin (Maizels and McCargerb, 2005). Holistic Pain Treatment Methods Modern medicine has a limited number of answers to the treatment of chronic pain. As a result, holistic modalities in the treatment of various forms of chronic pain are becoming increasingly integrated into the ma instream of patient care (Dossey, 1998). The most commonly practiced complementary medi cine includes mind-body therapies. This encompasses cognitive behavioral methods, hypnosis Qi Gong, and meditation (Berman, 2003). In 1997 the National Inst itute of Health endorsed acupuncture (when used alone or as a part of a comprehensive management program) as a promising technique for pain alleviation. They define a holistic perspect ive as one that consid ers the whole person, including physical, mental, emotional, and spiritual aspects (Dossey, 1998). In many cases, a multidisciplinary approach including some form of stress management, coping skills training, cognitiv e restructuring, education, and possible relaxation therapy is helpful for patients with chronic pain, especially chronic lower back pain. Other methods such as hypnosis, group therapy, relaxation, and imagery can lower recovery time and be used to alleviate pain when used in childbirt h, pre-operatively, or

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21 even during invasive medical procedures (Berman, 2003). In 2006, David Rhodes wrote his senior thesis on the remediation of pain through hypnosis. He found no empirical evidence of disproving the clinical use of hypnotism for pain relief. Rather, his sources agreed that the use of hypnosis is very succe ssful in a wide percentage of subjects. Rhodes also wrote that there is no specific neural switch linking hypnosis interference with the transfer of pain signals. His personal view was that the neural signals remain the same while the attentional focus shifts to a different topic in consciousness. Although there is very limited research on its usefulness, acupunc tures credibility as a pain treatment had been enhanced by basic science experime nts showing that the needles release endorphins and other neur otransmitters in the brain (Rosted, 2000). Needling the appropriate position of the 361 traditional acupuncture points is proposed to rebalance the bodys functioning by contacting th e vital energy Qi (Leibing et al., 2002). Some of the strongest pro-acupuncture clin ical research has been centered on the treatment of dental and tem poromandibular dysfunction pain (Rosted, 2000). This will be further addressed in the third chapter of the thesis. Herbal medicine used to treat pain has gained some support from trials in patients with rheumatoid arthritis In these trials the use of linolenic acid (which is found in borage seed oil and black currant seed oil) was used. Avocado, soybean unsaponifiables chondrotin sulphate, glucosamine S-adenosylmethionine (SAMe), and devils claw have all been shown to be effective in treating osteoarthritis pain (B erman, 2003). There is particularly strong evidence for the use of Hyben Vital (a standardized dry powder made from Rosa canina) as an effective treatment for lo wer back pain (Rain et al., 2004).

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22 In conclusion, the knowledge of pain that the scientific co mmunity has acquired up until now is light-years ahead of where it was only 100 years ago. Modern technology has allowed the understanding of pain pathways and how nociceptors work in the body. Using this knowledge, methods for diagnosing pain have been established with several different rating scales that have been altered to fit any type of patient regardless of mental capabilities. Clinical and holistic pain trea tments have their own research journals dedicated to them, proving how far the study of pain has come. Modern pain treatment methods range from medicinal plants to s ynthesized pharmacological compounds that act on the bodys physiological reaction to painfu l stimuli. Present knowledge of the human body cannot conquer pain as a whole but is getting closer by the day.

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23 Chapter 2: Orofacial Pain [An Overview] This chapter is designed to touch upon the basic features related to orofacial pain and expose the gaps in research that will be further addressed in the conclusion. Leading with the anatomical descript ion of the trigeminal brainstem nuclear complex (VBSNC), the relays of nociceptive transm ission from the brainstem to the thalamus and ultimately the cerebral cortex will be explored. The sec ond half of the chapter is dedicated to the most common disorders linked to orofacial pain and details a popular biopsychosocial assessment model currently used by some phys icians. The research that informs this chapter illustrates that while modern science has a grasp on how to treat orofacial pain through pharmacological methods, the etiology and physiological mechanisms behind trigeminal nerve disorders remain vastly unexplored. Trigeminal Nerve Anatomy As discussed in the first chapter, orofaci al pain transmission occurs through the trigeminal nerve. In fact, the various branches of the trigeminal nerve mediate the greater part of sensory innervation in the face (Liebgott, 2001). These branches are the ophthalmic nerve, the maxillary nerve and the mandibular nerve. Together, all three branches innervate all orofacial tissues. Figure 2 illustrates how the trigeminal nerve appears as a thick trunk with a smaller compone nt arising ventrolaterally with respect to the pons of the brain. The nerve passes anterior ly over the temporal ri dge and dives into Meckels cave Within the cave, the nerve flattens to become the large trigeminal ganglion and separates into its three branches (Moore and Dalley, 2006). The ophthalmic nerve passes through the superior orbital fussure and then divides into three branches

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24 (lacrimal, frontal, nasociliary ). The second branch, the max illary nerve, passes through the cavernous sinus and the foramen rot undum. The mandibular nerve runs through the foramen ovale and then splits into anterior and posterior directions (Liebgott, 2001). While all three branches of the trigeminal nerve are sensory nerves, the mandibular nerve is also linked to motor functions. Motor bran ches of the mandibular nerve are found in the anterior division of its bifurcation and supply temporalis, masseter, and lateral pterygoid muscles (Hiatt and Gartner, 2002). The Trigeminal Brainstem Nuclear Complex The driving force behind nociceptive tran smission in the orofacial region lies within the VBSNC. It is through this complex that informati on is first processed and then relayed to other parts of the central nervous system (Kapur et al., 2003). The supportive evidence of this is rooted in studies util izing clinical, behavi oral, morphological, and electrophysiological approaches. For example, there have been several consistent findings in experimental anim als that disruption of the ca udalis region of the VBSNC, either surgically or chemical ly, can interfere with an animals apparent perception of a noxious stimulus to certain parts of the craniofacial region (for further evidence, see Sessle, 2000). The VBSNC is a bilateral multinucleated structure lo cated in the dorsolateral brainstem (Figure 3). The complex extends fr om the pons to the upper cervical spinal cord. Subdivisions occur as the main, or prin cipal, sensory nucleus and the spinal tract nucleus, which consists of three subnuclei (o ralis, interpolaris, and caudalis) (Moore and Dalley, 2006). Morphological evidence shows that caudal components of the VBSNC

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25 highly resemble the spinal dorsal horn, a pivo tal area of the spinal cord, which, according to the gate control theory of pain, is responsible for relaying spinal nociceptive information from spinal primary afferents (Sessle, 2000). This is more reasoning behind the VBSNC being highly linked to nociceptive transmission. The neurons in each nucleus and subnucleus are somatotopically arranged. In this case the neurons with an oral or perioral receptive field are found in the most medial part of the main sensory nucleus and each of th e three subnuclei. In subnucleus caudalis, however, this representation of the face and m outh is slightly altered, in that perioral regions tend to be represented in the rostral part of the subnucleus and more lateral regions of the face are seen more ca udally (Hiatt and Gartner, 2002). The ventral components of the nucleus and three subnuclei are composed mainly of neurons with a receptive field in the orofacial region (Sessle, 2005). The ophthalmic branch of the trigeminal nerve innervates this particul ar region (Liebgott, 2 001). The dorsal part contains neurons with mandibular receptive fi elds, and the area between the ventral and dorsal parts of the main sensory nucleus and each subnucleus contains neurons with maxillary receptive fields. (Sessle, 2000). Mechanisms of Orofacial Pain Important anatomical structures aside, it is the way in which these components function which creates the pathway for nocic eptive transmission. The primary afferent cell bodies of most trigeminal nerve afferent s innervating cutaneus, intraoral, deep and cerebrovascular tissues are located in the ganglion (S essle, 2000). Each of these cells has an axon which stretches from the ganglion to th e peripheral tissues (known as the primary

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26 afferent fiber) and another axon wh ich projects centrally into the ipsilateral brainstem, where it connects with other neurons in se veral components of th e VBSNC (Cahana and Forster, 2006). The Importance of Subnucleus Caudalis As already mentioned, the somatotopical arrangement seen throughout the VBSNC is somewhat altered in subnucleus caudalis. Instead of having an inverted, medially-facing somatotopic pattern, the subnucleus caudalis periorial regions are represented rostrally and lateral regions of th e face are seen more caudally than expected (Dubner and Ren, 2000). Subnucleus caudalis receives afferent inputs from both sides of the face and mouth. Studies of the rostral and caudal components of subnucleus caudalis have shown they possess unique morphological and functional featur es contributing to perceptual, autonomic, hormonal and muscle reflex responses to noxious stimuli in orofacial tissue (for more informa tion, see Bereiter et al., 2000). The scientific community has found a considerable amount of supportive evidence to the idea that subnucleus caudalis is the principal brainstem relay site for trigeminal nociceptive information. To begin with, trigeminal nerve tractotomies (neurosurgical transections of the trigeminal nerve spinal tract at the rostral end of subnucleus caudalis) have been used in the past to relieve trigeminal neuralgia in humans. It has been shown the procedure also causes a marked reduction in the patients ability to perceive noxious stimuli, especi ally when applied to the face (Svensson and Graven-Nielsen, 2001). Comparable procedures resulting in similar lesions have been performed on animals, resulting in reduced behavioral, autonomic and muscle reflex

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27 responsiveness to faci al stimuli (Dubner and Ren, 2000). These observations suggest that a lesion on the caudalis interferes with the relay of nociceptive signals from the nociceptive primary afferents to the sec ond order neurons in subnucleus caudalis. Secondly, a great majority of the A and C-fiber primary afferents that carry nociceptive information from the various orof acial tissues all terminate in subnucleus caudalis. These smaller afferents terminate ma inly in caudalis laminae I, II, V, and VI. The larger A-fiber primary afferents terminate primarily in laminae III-VI of caudalis as well as in the more rostral components of the VBSNC (Moore and Dalley, 2006). Also, the laminated structure of subnucleus caudali s is a morphological distinction from the other 3 components of the VBSNC, which have a more uniform structure. This uniqueness resembles the dorsal horn of the spin al cord, which is critically involved in nociceptive transmission from the limbs, trunk, and neck (Cahana and Forster, 2006). Fourthly, the chemical mediators (glutamate, substance P ) and receptors ( NMDA neurokinin ) involved in nociceptive transmission a ll predominate in subnucleus caudalis compared to other parts of VBSN C. This is also the case with immunocytochemical markers of neuronal activity, such as c-Fos protein (Sessle, 2005). Lastly, electrophysiological recordings of the activity of brai nstem neurons in animal experiments have also rev ealed that many neurons in caudalis can be activated by cutaneous nociceptive inputs and th at they are predominantly located in the superficial (I, II) and deep (V, VI) caudalis laminae, whic h, as mentioned above, are where the fifth nociceptive primary afferents terminate in the VBSNC (Svensson and Graven-Nielson, 2001).

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28 However, subnucleus caudalis is not th e only component of the VBSNC that plays a role in orofacial noci ceptive processing. It is simply the most researched. There is also evidence that points to the involvement of the rostra l components, subnucleus oralis and interpolaris, but th is evidence is scarce and lacks the amount of scie ntific backing that has been done on caudalis. The limited amou nt of information that has been studied includes findings that lesions of rostral co mponents may disrupt some orofacial pain behaviors, and that many neurons in subnucle us interpolaris and oralis project to brainstem or higher brain centers involved in reflex or perceptual aspects of orofacial pain (Sessle, 2005 and 2000). Also, interpolis and oralis can be act ivated by stimulation of tooth pulp or other sites, such as facial musc le. These neuronal features suggest that the more rostral components of the VBSNC ma y play a role in pe rioral and intraoral nociceptive processing (Dubner and Ren, 2000). Thalamic and Cortical Neural Mechanisms When compared to the work done on brai nstem mechanisms, there has been much less research focused on higher brain proces sing of orofacial nociceptive processing. The thalamic regions that receive and relay or ofacial somatosensory information from the brainstem include the ventroba sal complex (in humans, the ventroposterior nucleus), a posterior grouping of nuclei, and the medial thalamus. Just like what is seen in the brainstem, in the thalamus, glutamate is crucial to the transmission of somatic signals. It is released from the thalamic terminals of axons of the fifth brainstem neurons which acts, through glutamate receptors, to activ ate the neurons (Lewis et al., 2007).

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29 As seen in the VBSNC, the ventroba sal thalamus is also somatotopically organized. The neurons receiving and relaying tactile information from the face and mouth can be found in the medial portion of th e ventrobasal thalamus (Al-Chaer et al., 1998). The lateral part of the ventrobasal th alamus receives somatosensory information from the limbs, trunk and neck, prim arily via the dorsal column-medial lemniscal system and the spinothalamic tract Most signals are passed from the brainstem to the overlying somatosensory areas of the cerebra l cortex (Lewis et al., 2007). The thalamus itself also contains nociceptive neurons. Nociceptive neurons fall under two categories, nociceptiv e specific (NS) and wide dynamic range (WDR). Both NS and WDR neurons are seen in the mo re rostral subnuclei and have cutaneous receptive fields localized to perioral or in traoral areas (Svensson and Graven-Nielsen, 2001). In general, the neurons located in the thalamus are both NS and WDR. Some of these neurons, similar to their br ainstem counterparts, respond to musculoskeletal, cerebrovascular or tooth pul p stimuli as well as cutaneous stimulation (Duber and Ren, 2000). Nonetheless, many neurons seen in the ventrobasal thalamus have receptive fields, response properties, and connections with th e overlying somatosensory cerebral cortex. These facts indicate a role in the sensory di scriminative dimension of pain (Al-Chaer et al., 1998). On the other hand, nociceptive neurons found in the more medial nuclei of the thamalus are more involved in the affective or motivational dimensi ons of pain, and are connected with other higher brain areas such as the hypothalamus and anterior cingulate cortex, both of wh ich participate in neuroendocrine responses related to pain (Lewish et al., 2007).

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30 Nociceptive neurons responding to noxious orofacial stimuli are also seen in the cerebral cortex. Like its subcortical counterparts, the cere bral cortexs primary somatosensory area contains both NS and WD R neurons. It responds to noxious stimuli in a manner indicating a role in the sensor y-discriminative dimension of pain, including location and intensity of stimulation in th e face and tooth pulp (Cahana and Forster, 2006). Nociceptive neurons are not limited to the somatosensory cortex, they also occur in the anterior cingulate cortex and insula Both of these regions have been linked to the affective, attentional and motivational aspects of pain rather than the sensorydiscriminative dimension of pain (Sessle, 2005). Reflex and Behavioral Mechanisms As detailed above, many neurons in the VBSNC relay information to the brainstem or other higher brain centers involved in reflex or more complex responses to noxious orofacial stimuli. Orofacial pain is associated with reflex changes in blood pressure, heart rate, breathing, and saliva tion induced by noxious stimulation. Several behavioral paradigms have been develope d in humans and animals based on these autonomic responses in order to better unders tand the effects of noxious orofacial stimuli (Kapur, 2003). The human behavioral paradigm s also include measures of more complex behavioral responses such as facial expressions and subj ective reports (such as the McGill Pain Questionnaire). There have been limited amounts of rese arch performed on reflex circuits and sensorimotor mechanisms. Some findings sugges t that neurons (especially in the rostral components of the VBSNC) are involved in the reflex circuits underlying the jaw

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31 opening reflex (Sessle, 2005 and 2000). The sm all amount of research accomplished has shown that subnucleus caudalis is crucial in reflex responses (cardiac, adrenal or respiratory changes) to noxious orofacial stim ulation. These region is also involved in the prolonged nociceptive reflex responses of jawopening and jaw-closing muscles that can occur following noxious stimulation of the te mporomandibular joint. The most caudal region of the VBSNC also contributes to mo re complex pain-avoidance behaviors that can be evoked by noxious orofacial stim ulation (Cahana and Forster, 2006). Disorders Linked to Orofacial Pain Now that the anatomy and mechanisms linked to orofacial pain have been presented, the topic will shift to the clinical conditions that are associated with VBSNC pain transmission. The main focus will be on dental pain, pre-trigeminal neuralgia, temporomandibular disorder, burning mouth syndrome, and phantom tooth pain. All of these conditions have comprehensive guidelines for treatment while some lack necessary information such as transmission mechanisms or concrete qualifications for diagnosis. Dental Pain Of all the complaints surr ounding orofacial pain, tooth/de ntal pain is the most common. Much of this is due to neglect; rarely it is seen to be indu ced inadvertently by a physician or surgeon or by medical treatment or diagnosis procedur es (Kapur et al., 2003). The treatment of such pain often results in the repair of fractured teeth with proper cavity preparation, cavity excavation and the physical restora tion of the offending tooth (or teeth). However, it is not uncommon for th e issues to extend further than the tooth proper: the dental pain being experienced may be linked to endodontic or periodontal

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32 issues or both. An example of this would be a patient with mobile teeth that become painful while chewing, or a tooth that has had previous carious restoration treatment but, because of inadvertent iatrogenic exposure of the dental pulp, the area has become infected and now requires a root canal (Ide and Kusama, 2002). Another cause of dental pain is verti cal fracture lines present on the tooths enamel These fractures prove to be very pa inful and escape some physicians because they are difficult to diagnose and physically visualize (Roste d, 2000). Typically, the physician will firmly tap each tooth (referred to as percussion ) until the offending tooth is located. Occasionally, the patient presents w ith referred pain on the opposing jaw. Again, percussion may be used to localiz e the offending tooth (Kapur, 2003). There are some relatively simple technique s that may be used by a dentist to delay a patients pain prior to treatment. Prophylactic treatments often consist of nonprescription analgesics such as acetaminophen or ibuprofen in alternating doses. Prescription narcotics containing either codeine or oxycodone can also be helpful, especially in combination with NSAIDs such as ibuprofen or naproxen (Ide and Kusama, 2002). Topical analgesics may also be used to subside dental pain, provided the dental pulp is not in direct contact with the analge sic. The most well known topical analgesic in the US, Ambesol has proven to be paradoxically, very effective at increasing dental pain if the pulp is exposed (Lewish et al., 2007). An additional treatment for dental pain consists of locally blocking the perturbed to oth or teeth. This is accomplished through the use of local anesthetics, which is a main focus of the third chapter. Trigeminal Neuralgia and Pre-Trigeminal Neuralgia

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33 The term neuralgia describes unexplain ed peripheral nerve pain. The head and neck are most affected by said neuralgias (Bagheri et al., 2004). Trigeminal neuralgia (TN), also referred to as tic douloreux (painful jerking), is a ch ronic pain condition that affects the trigeminal nerve, resulting in recu rrent facial pain (Sessle, 2000). Due to the fact that TN is categorized as a facial pain disorder rather th an an orofacial pain disorder this section will not be as in-depth as the other conditions being covered. TN is characterized by paroxysms of intense, electric-like bouts of pain restricted to the area innervated by the trigeminal nerve. The pain predominantly occurs unilaterally and is more commonly noted on the ri ght side. Pain transmission involves the mandibular and/or maxillary branch and is rarely seen in the ophthalmic branch. The attacks occur spontaneously fo r a few minutes and in most cases can be triggered by a nonpainful stimuli applied to the surrounding skin or mucosa (Kapur et al., 2003). Pre-trigeminal neuralgia (PTN) is TNs prodromal counterpart. PTN is a pain syndrome in which patients experience a dull, continuous, aching or burning pain in the upper or lower jaw for a long period of time (Cruccu et al., 2007). Patients with PTN normally describe their pain as sinusitis-li ke or resembling that of a toothache. The pain lasts up to several hours and is tri ggered by some type of jaw movement (be it yawning or masticating) or e xposure to hot or cold drinks. There are no definite trigger areas of the skin or mucous membrane in PTN patients (Zvartau -Hind et al., 2000). The pathophysiologic mechanisms of bot h TN and PTN remain unclear and not entirely explored. Several hypotheses have b een stated, including traumatic compression of the trigeminal nerve by neoplastic or vascular anomalies (e.g. tumors), infectious

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34 agents (including the human herpes virus), and demyelinating conditions (such as MS) (Zvartau-Hind et al., 2000). One popular explanation coincides w ith the neuromatrix theory of pain and proposes that these diseas es arise secondary to a vascular loop that crosscompresses the trigeminal nerve a fe w millimeters proximal to the pons (Kapur, 2003). Despite these hypotheses, there is still no universally accepted medical explanation for TN or PTN. The diagnosis of PTN is difficult because it is easily confused with other causes of facial pain, specifically those of dental or igin. As seen with TN as well, the patients clinical history is the most valuable tool for diagnosis. The description of the typical prodromal pain in a patient with normal ne urological and dental examinations provides the basis for the diagnosis of PTN (Burch iel and Slavin, 2000). A physician may also recognize PTN using typical radi ological studies such as MRIs or computed tomography scans, along with a therapeutic response to carbamazepine (an anticonvulsant) or baclofen (a muscle relaxer). Both of thes e medications are effective in managing PTN and TN (Cruccu et al., 2007). In fact, patients treated with carbamazepine may remain pain-free even after tw o years of stopping the medication. However, symptoms have been reported to recur after that time (Burchiel and Slavin, 2000). Burning Mouth Syndrome Burning mouth syndrome (BMS) is characterized by burning and painful sensations in the oral cavity in the abse nce of abnormalities (Kapur, 2003). In addition to the burning sensation, patients report of a dry/ sore mouth and numbing tingles throughout the mouth and anterior two thirds of the t ongue. Burning is always reported as bilateral

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35 and symmetrical. A bitter or metallic taste may also be experienced if one has BMS (Klasser et al., 2008). The disorder has been li nked to a variety of other conditions, such as menopause, tongue thrusting, acid reflux, a nd psychological problems. Some research suggests a dysfunction in the trigeminal nerv e is the causation. However, this hypothesis has never been thoroughly invest igated (Kapur et al., 2003). Even though the physiological mechanisms of BMS have yet to be discovered there are still treatment options available. No rmally the treatment is directed towards any underlying cause (Zakrzewska et al., 2004). This may entail reversing nutritional deficiency, rinsing with diphenhydramine or, if Candida has been isolated, the use of a topical antifungal such as clotrim azole (Bergdahl and Bergdahl, 1999). Temporomandibular Disorders The term temporomandibular diso rder (TMD) encompasses a group of musculoskeletal problems that affect the temporomandibular joint (TMJ) and/or the muscles used for mastication These problems lead to orof acial pain, joint noise, and restricted jaw function. Patient s describe the pain as a dul l ache not associated with paresthesias nausea, or visual disturbances; typically the painful sensation is located in the preauricular region (Warren and Fried, 2001). The three most common TMDs are myofacial pain and disfunction, disk displa cements, and osteoarthrosis. Muscle-related conditions account for more than 50% of reported cases of TMD, resulting from detrimental oral habits such as bruxism or severe jaw clenchi ng. Anxiety, depression, and stress levels are also associated with exacerbating these disorders (Kapur et al., 2003).

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36 Disk displacements, also known as intern al derangements, is a type of TMD in which the articular disk in not in its normal positioning, resulting in mechanical interferences and mandibular restriction. Ther e have been some hypotheses formed such that direct trauma to the jaw may play a role in disk displacements. However, this has not yet been proven and other studies suggest that trauma does not increase the incidence (Greene, 2001). Osteoarthrosis, a degenerative disorder associated with the articular cartilage of the TMJ, is mostly seen in ol der populations (Wa rren and Fried, 2001). The etiology behind TMDs have yet to be resolved. Currently, most medical professionals believe that most cases are idiopathic Malocclusion trauma, and psychological factors are all considered exac erbating factors or po ssible causes. Also, muscle tension headaches and chronic pain in the head, neck, and jaws may predispose one to TMD via neuroanatomic and neurobiologic mechanisms. While these postulations appear to be logical explanations, there is no substantial evidence to back any of these claims (De Boever et al., 2000). Diagnosis for TMDs should be based on a historical, physical, and psychological assessment. Pain should be evaluated based on its onset, nature, intensity, location, and duration. Range of maximal vertic al opening should be recorded as a part of the physical evaluation (Warren and Fried, 2001). Panoramic radiographs are the standard screening test for the bony jaw structure witnessed with TMD (Bur chiel and Slavin, 2000). Pain management approaches vary with intens ity and typically fo llow a pharmacological regimen of medicines including NSAIDs, narco tics, muscle relaxants, antidepressants, anticonvulsants, and corticosteroids. There are also a limited number of surgical procedures that have proven effective (Kapur et al., 2003).

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37 Diagnostic Issues The most prevalent chroni c orofacial pain conditions are musculoskeletal related TMD and neuropathic (examples being TN and PTN) pain conditions (Higginson 2002). Unfortunately for the patient, chronic orofacial pain is resistant to quick resolution because the amount and location of pain expe rienced and the behaviors of the patient showcased while dealing with said pain are poorly related to physical events, causing etiology to be individual to the case a nd treatment to be difficult (Mostofsky, 2006). Persistent pain in the muscles used in mastication may be a minor inconvenience to some or a decades-long, source of depression in othe rs. Yet, there may be no detectable, not to mention diagnosable, physical change to differentiate the two. Th erefore, whether the persistent pain is viewed as a minor inconve nience or a major source of life stress to the patient, chronic orofacial pain often cannot be understood in terms of diagnosable pathology (Higginson, 2002). Biopsychosocial Model for Orofacial Pain Diagnosis While diagnosis is not an exact science, there are still models available that work toward conceptualizing a pati ents orofacial pain. The assessment methods addressed in the first chapter hold true for the more sp ecific challenge of di agnosing pain centered around the mouth. In order to expand upon cove rage in the previous chapter and what was mentioned in the introduction, a biopsychos ocial model for chronic orofacial pain will be discussed. The biopsychosocial model is illustrate d in Figure 4. The models five-stage process integrates physi ological activity with associated psychological states and socially

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38 and culturally determined behavior (Lewish et al., 2007). All of the st ages reflect normal or adaptive mechanisms by which individuals come to experience pain, attempt to make sense of said pain and create behavioral adap tations. Brief explanations for each level are as follows: Nociception: Physiological events witnes sed during pain transmission that, among other things, lead to the transmission of pain information to the VBSNC. Perception: Identified as the initial stag e of forming a subjective pain response, this stage encompasses the pa tients self-identif ication of the phys ical qualities of pain, which includes spatial (localized or diffused), sensory (examples include sharp, dull, or throbbing), and temporal (recent onset or recurrent sensation) descriptions. Appraisal: Higher order me ntal operations attaching cognitive and emotional meaning to the pain. This level is crucial for attaching the patients verbal description of pain sensati on to the physical experience. Behavior: Observable pain behaviors that either contribute (for example, teeth grinding) or are a result of the pain (inactivity, diet restrictions) Sick Role: This level evaluates the influence of social factors that play in determining observational pain manife stations, such as gender variation. Treatment options for dental and orofacial pain are often constrained by social or cultural factors, such as availability of health insurance and government regulation of narco tic analgesics.

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39 For a more comprehensive evaluation and description of the biopsychosocial model of pain assessment, see David Mostofsky and colleagues book Behavioral Dentistry, 2006. To conclude, nociceptive transmission that leads to the sensation of orofacial pain is relayed from the trigeminal nerve to the brainstem, which leads to the thalamus and eventually crosses into the cerebral cortex. The sensitization of th is process leads to orofacial pain disorders including burn ing mouth syndrome and pre-trigeminal neuralgia. While the pathophysiology of these disorders remains poorly understood, pharmaceutical companies offer many treatmen ts. In the process of treating these disorders, physicians and dentists ma y use assessment methods such as the biopsychosocial model or the McGill Pain Questionnaire. Overall, orofacial pain, especially in chronic form, remains a topic for scientists to explore in the years to come.

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40 Chapter 3: Dental Analgesics Pain and anxiety control have always been linked to the realm of dentistry. In fact, in 1795 Humphrey Davy (at the age of 17) bega n the first experimentation with nitrous oxide in order to relieve a toothache (Lei tch and Macpherson, 2007). Ever since then, many of the pioneering experiments in anesth esia, be it local or general, have been carried out by dentists. The massive amount of fe ar and anxiety that is linked to visiting the dentist leads to the avoidance of treatme nt, which in turn may result in increased levels of dental disease. For the sake of this thesis, fear may be considered the physiological process that occurs in the body when threatened by danger, where as anxiety is the anticipa tion of the possibility of danger a nd is classified as less immediate in nature (Chanpong et al., 2005). In 2000, Cohen and colleagues published an article entitled "The impact of dental anxiety on daily living." In this article he concluded that dental anxiety has far reaching effects on patients' quality of life, including sl eep disturbance and interference with work and personal relationships. The article included a survey of patient preferences in the United States and the results found that 65% of those asked would like to remain painfree but conscious during dent al treatment, and 56% woul d prefer to be rendered unconscious for treatment. Thanks to modern analgesic techniques ei ther one of these options (conscious and unconscious) is possible. The use of pharmaceu ticals to help patients cope with their fear/anxiety of dental treatment has been exte nsively researched, resu lting in a number of techniques used in dental practices today. This chapter will review the more innovative

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41 analgesic treatments currently being used on dental patients, emphasizing the chemicals used and what is currently known of their pharmokinetic properti es and physiological mechanisms of action. Inhalation Anesthesia From the discovery of anesthesia to the pr esent, inhaled anesthetics have acted as the primary means for anesthetic delive ry (Eger, 2005). The intimate relationship between nitrous oxide (N2O) and oxygen (O2) inhalation and dentistry has existed for over 200 years. There are many a dvantages of administrating N2O/O2 sedation during dental procedures, including: pleasant respons es from patients, rapid and deep analgesic effects while leaving the patient cooperative, and quick elimination from the body (Sutton, 2003). It is estimated that more than 50% of general dentists and nearly 90% of pediatric dentists administer N2O/O2 to their patients to allevi ate pain and anxiety (Clark and Brunick, 2003). This section will cove r the important physical properties and pharmacokinetics of N2O. N2O is relatively insoluble with a blood-gas partition coefficient of 0.47. It easily crosses the alveolar membrane and remains unchanged in the blood without combining with any blood elements (Lahoud and Aver ley, 2002). Uptake by the blood is limited, signifying that equilibrium is quickly achieved and peak clinical effects may be seen within 5 minutes after inha lation (Sutton, 2003). Other part ition coefficients of N2O between muscles, tissues, and fat are low as well. Once again, equilibration occurs quickly because of the inability of the tissues to hold N2O. As a result, N2O is not stored in the body to any extent; thus elimination is not abated (Eckard et al., 2006).

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42 The potency of a drug is determ ined by the assessment of the minimum alveolar concentration (MAC). MAC is further defined as the amount of drug necessary to prevent movement in 50% of subjects res ponding to surgical in cision (Lahoud et al., 2000). N2O is the weakest of all inhalation gene ral anesthetics and has a MAC value of 104% to 105%. The value indicates that at normal atmospheric pressure N2O alone is not able to produce profound surgical anesthes ia (Clark and Brunick, 2007). The high MAC value and limited potency of N2O massively add to its safe use in the body. Sevoflurane is another inhalation agent with proven analgesic effects. Currently, it stands behind N2O as the most widely used inhaled an esthetic and has proven to be more effective than N2O alone (Lahoud and Averley, 2002). Sevoflurane has a MAC value of 1.7% and a blood-gas partition coefficient of 0. 68 (Clark and Brunick, 2007). Thus, it is more potent than N2O and does not exit the body system as quickly. However, one must take into account, when sevofluranes blood-ga s partition coefficent is compared to other inhalation agents, it is still relatively low, implying that it easily leaves the body after inhalation. A study by G. Lahoud, P. Averlry and M. Hanlon in 2001 investigated the efficacy of sevoflurane in combination with N2O/O2 as a conscious sedation technique to be used on children. Out of 75 children, 69 (92%) were able to undergo successful treatment without having to resort to general anesthes ia. In 2002, G. Lahoud and P. Averly completed another study in 441 ch ildren that tested the efficacy of a sevoflourane/nitrous oxide mixture compared to nitrous oxide alone. Dental treatment was satisfactorily completed in 215/241 (89%) of the children given the mixture and only 89/170 (52%) who were given just N2O. In both studies, no adverse side effects were

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43 witnessed, along with no differences in oxygen saturation, heart rate, recovery profile, nor time until discharge. They both concluded that the use of sevoflurane in low concentrations to supplement N2O/O2 conscious sedation in children is safe and effective. Unfortunately, the exact mechanism behind how N2O or sevoflurane depresses the central nervous system, causing anal gesic effects, remains unknown. In 1986, M. Gillman proposed that analgesic concentrations of N2O may act directly on the opioid receptors and/or activate the release of endogenous opiates that are seen during pain transmission. It has been found that anesth etics act by one of tw o mechanismsblockade of NMDA glutamate receptors or enhancem ent of CABAergic inhibition1. P. Nagele trumped Gillmans theory in 1999 when he found that N2O, inhibits both ionic currents and excitotoxic neurodegeneration mediated through NMDA receptors. These theories are steps in the right direction but the exact mechanism of action of nitrios oxide remains unknown. Nageles theory was published a decade ago and there have been no articles published on this matter since. Also, ther e have been no published theories on the pathway that sevoflurane utilizes to produce pain-reducing effects. Intravenous Sedation Inhalation anesthetics are used as a precursor to intravenous anesthesia. The inhalation anesthetics produce varying degr ees of analgesia and skeletal muscle relaxation, allowing patients to be more at ease when the IV is inserted (Eger, 2005). Sedation falls into four categories: minima l (conscious) (patient responds normally to tactile stimulation and verbal command), moderate (patient responds purposefully to verbal commands, either alone of with the help of some light tact ile stimulation), deep

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44 (patients cannot be eas ily aroused but respond purposefully following repeated or painful stimulation, patient may require assistance in maintaining airflo w) and general (patient is not arousable, even by painful stimulation and has an impaired ability to independently maintain ventilatory function) (Royer and Paarmann, 2007). The exact mechanism of all types of seda tion remains controversial, but the main theories postulate that anesthetics may influence synaptic transmission by potentiating neurotransmitter release at inhibitory synapses or by i nhibiting excitatory synapses (Dionne, 2001). Despite modern medicines poor understandi ng of anesthesia at the molecular level, there has been extensive re search on the effects produced by the variety of drugs used to accomplish the varying leve ls of sedation (Boynes et al., 2006). There is no single pharmaceutical agent with all the requirements for a complete anesthetic. Rather, a cocktail of hypnotics (barbiturates, propofol, benzodiazepines), ketamine and opioids is used to obtai n the desired effects. Firstly, sedative hypnotics are used to induce unconsciousness. Most commonly, ultrashort-acting barbituates, propofol, and benzodiazepines are used. These agents have high lipid solubility ensuring a rapid onset of action (Dionne at al., 2003). Pharmacologically speaking, these chemicals are sedatives, not anesthetics, and they are used for conscious sedation (Royer and Paarma nn, 2007). Barbiturates, such as thiopental and methohexital, produce their hypnotic effect by mixing with gamma-aminobutyric acid (GABA). They potentiate the action of GABA receptors and directly effect chloride ion conductance (Leitch and Macpherson, 2007) All sedative hypnotic s are metabolized in the liver into inactive, water soluble mol ecules that are excreted in urine. Propofols action sequence is similar to that of the barbitur ates. Its only distinguis hing feature is that

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45 besides being metabolized by the liver, pr opofol is also broken down by multiple tissue sites that have yet to be clea rly defined. Therefore, it has a much faster systemic clearing rate when compared to barbiturates (Strunin, 2007). Diazepam, lorazepam, and midazolam comprise the benzodiazepine catego ry. Midazolam is the most popular and is also used as an oral premedication that wo rks to reduce surgical stress. Benzodiazepines are the only class of sedatives with a known antagonist flumazenil, and do not affect respiratory or cardiovascular function as severely as barb ituates (Dionne at al., 2003). However, midazolam may not lie at the top of the dental sedation ladder. In 2006, Ustun et al conducted a study testing the sedativ e, analgesic and anxi olytic properties of midazolam and dexmedetomidine His study reports a sta tistically significant improvement in patient cooperation and VAS scores for patient satisfaction in the dexmedetomidine group. Very little work has been performed on this drug and Ustuns results suggest it warrants further study. The second addition to the common anesthetic cocktail is ketamine. Of all of the intravenous agents, ketamine comes closest to standing alone as a complete anesthetic (Leitch and Macpherson, 2007). The drug produc es a unique form of unconsciousness described as dissociation. When under the infl uence of ketamine many patients keep their eyes open and emerge with a sense of delirium Ketamine stimulates sympathetic outflow from the central nervous system and inhi bits neuronal uptake of norepinephrine and NMDA receptors. Like the other agents already discussed, ketamine is metabolized in the liver and is excreted in ur ine (Royer and Paarmann, 2007).

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46 The final addition to a seda tion cocktail is an opioid. Opioids, such as fentanyl and hydrocodone, are included to provide analge sia and offset sympathetic responses to stimuli. They work by stimulating opioid receptors, which subserve the endogenous analgesia system (Sutton, 2003). All component s of the cocktail shou ld be mixed based on the patients weight, with specia l considerations taken for children. Local Anesthesia As important as sedation is, effective de ntal treatment without the use of local anesthetics is virtually impossible. In 2005 it was estimated that in the United States alone, local anesthetics were administered 350 millions times for dental-related situations (Horowitz et al., 2005). The first local anes thetic, cocaine, was discovered in 1860. While proven effective, cocaines inhibition of dopamine reuptake, resulting in euphoric feelings, greatly increases its potential for abuse. In 1905, procaine (Novocain) became readily available and quickly gained wide acceptance in the dental community (Blanton and Jeske, 2003). Its popularity declined in 1948 with the invention of lidocaine, which remains the most widely used local anesth etic agent today (Baar t and Brand, 2008). This section includes the pharmacology of local an esthetics, along with a description of the methods of administration and complicati ons seen in the modern dental world. Classification Local anesthetics are the most commonl y used pharmaceuticals in the realm of dentistry (Lustig and Zusman, 1999). Common characteristics seen in the molecular structure of all local anesthetics include a lipophilic, aromatic group that contains a benzene ring and intermediate ester or amide chain, and a hydrophilic, amino group tail. This is illustrated in the following pharmaceuticals:

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47 Procaine Lidocaine The lipophilic group determines the chemicals lipid solubility while the degree of water solubility depends upon the hydrophobic second ary or tertiary amide group (Greco and Conti, 2008). The strength of a lo cal anesthetic is directly re lated to its lipid solubility, dissociation constant, chemical linkage, a nd protein binding capab ilities (Blanton and Jeske, 2003). If carbon groups are ad ded to the structure, these strength factors are greatly affected (Baart and Brand, 2008). Local anesthetics are classified base d on the molecular structure of their intermediate chain; they may either be ami no-esters (such as procaine) or amino-amides (seen above as lido caine) (Becker and Reed, 2006). The amide s can be further categorized into three subgroups: toluidines xylidines and thiophenes. Toluidines contain a benzene ring with a single methyl group and a secondary amine group ending. Xylidines are tertiary amines with an aromatic component th at has two methyl subgroups. Thiophenes, as the name suggests, contain a sulfur ring in the aromatic component (Vasconcellos et al., 2008). Examples of a ll three subgroups, along with their molecular structure, are as follows:

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48 Prilocaine (Citanest), a toludine Bupivacaine (Marcaine), a xylidine Articaine (Ultracain, Septanest ), a thiophene Pharmacokinetics As a whole, local anesthetics are unstable, weak bases with poor water solubility (Malamed et al., 2000). With a single exception (a rticaine), they are tertiary amines and the addition of hydrochloric acid (HCl) converts this amine (expressed as R3N) into a chloride salt: R3N + HCl R3NH+ + ClThe addition of HCl increases the stability and water solubility once the reaction reaches equilibrium: Ka: R3NH+ + H2O R3N + H3O+

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49 In this case the R3NH+ ion represents the water soluble, quaternary cation form of the local anesthetic, which is responsible for the analgesic effects. The equilibrium constant, Ka, of most local anesthetic s is situated between 7 a nd 8 (Baart and Brand, 2008). Originating from the injection site, a local anesthetic must cross several barriers to reach the action site. For this to be accomplished, the uncharged base form (R3N) is necessary. This compound is lipophilic, enab ling it to pass through a neurons membrane (Royer and Paarmann, 2007). The lipophilicity is primarily determined by the charge of the molecule and (to a lesser extent) by the length of the carbon chain: the longer the chain, the greater the fat solubility (Lai et al., 2006). When the uncharged form reaches the inside of the cell, a new equilibrium w ith the water-soluble charged form is reached. The pH is lower inside the cell, so the equili brium will shift towards the active cationic form, R3NH+. Due to this fact, the proportion of both forms (R3N and R3NH+) plays an essential role in a local anesthetic s potency (Baart and Brand, 2008). A general rule underlying diffusion and penetration of the nerve membrane is that the closer the pKa of an anesthetic to the pH of the injection site, the higher the concentration of the uncharged base form (R3N) of the molecule (Becker and Reed, 2006). Therefore, choosing a local anesthetic with a low pKa or increasing the pH of the local anesthetic solution will increase the pe rcentage of the lipid-soluble uncharged form of the molecule. However, in order for diffusion to take place in the interstitial fluid between cells, the watersoluble ionized form (R3NH+) must be present in sufficient amounts. The presence of both forms in equilibrium is a common char acteristic of weak bases (Malamed et al., 2000).

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50 Local anesthetics block the developmen t of action potentials and conduction in the cell membrane. This is accomplished through the interruption of neural conduction by the inhibition of sodium ion influx. The lipophilic form (R3N) penetrates the lipid membrane, producing a structural change in the lipid bilayer and altering the conduction in the membrane of the neuron (Greco and Conti, 2008). This membrane expansion is only responsible for 10% of the total activity of lo cal anesthetics. The other 90% depends on the interaction between the cationic form (R3NH+) and the phospholipid phosphatidylL-serine in the membrane of the neuron (D ionne et al., 2003). When these chemicals come into contact, this leads to the closure of the sodium channels. The magnitude of a local anesthetics ability to close sodium ch annels is dependent on the frequency of the action potential (Blanton and Jeske, 2003). This entire process is referred to as conduction blockade or membrane stabilizati on and consists of a decrease in sodium conduction and a reducti on in the rate of depolarization When the channels are closed, the threshold potential level can no longer be reached and fulfilling an action potential is out of the question (B aart and Brand, 2008). As mentioned previously, the binding of plasma proteins varies with local anesthetics based on their chemical structure. When present in the blood stream, all local anesthetics reversibly bind to glycoproteins This degree of bindi ng correlates with the drugs affinity for the protein located within the sodium channels. The bond strength of the agent to the protein greatly determines how long a local anesthetic remains active in the body. In general, the higher the degree of binding to the glycoproteins, the longer the local anesthetic will remain active. The fraction of the protein bound to the local

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51 anesthetic acts as a transmission center, fr om which the free local anesthetic releases (Becker and Reed, 2006). Additives Aside from hydrochloric acid, vasoconstrictors and preservatives are added to local anesthetics to enhance effectiveness and improve poten cy. Local anesthetics, like most anesthetics (with mepi vicaine and prilocaine being the only two exceptions) produce vasodialation (Greco and Conti, 2008). Vasoconstrictors reduce the blood flow at the site of injection, delaying the rate of reabsorption and decrea sing systemic toxicity. Two common vasoconstrictors used in local an esthetics are adrenaline (also referred to as epinephrine) and felypressin a synthetic chemical derived from the antidiuretic hormone vasopressin (Sutton, 2003). The addition of vasoconstrictors does co me at a price. Their effect of reduced blood flow lengthens the heali ng process and lowers the pH of the tissue, reversing the equilibrium of the system to favor the ionize d form of the anesthetic. This decreases the penetration rate in the nerve and cancels a ll analgesic effects (B ecker and Reed, 2006). A third disadvantage is that a rebound effect might occur; meaning once the vasoconstrictors wear off there is a supply of degradation products and a sudden increase in blood flow increases the risk of secondary hemorrhage (Lai et al., 2006). Typically, the preservative bisulphate is included to prevent the oxidation of the vasoconstrictor. A disadvantage to this addition is that the bisulp hate decreases the pH of the solution and is a known allergen (Malamed et al., 2000). Elimination

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52 Local anesthetics are swept away from the inje ction site by the blood. The time taken for this to occur is dependent on the dosage amount and degree of tissue vascularization (Lustig and Zusman, 1999). On the syst ematic level, este r anesthetics are metabolized in plasma by the enzyme pseudo cholinesterase generating para amino benzoic acid analogues and amino alcohol The para amino benzoic acid analogues travel through the kidneys and are excreted in urin e while the amino alcohol undergoes further metabolization in the liver. Amide anesthetic s are metabolized in the liver starting with the cytochrome P450 system followed by conjugation This results in highly water-soluble metabolites that are later excreted by th e kidneys (Baart and Brand, 2008). Complications Even though dentists administer thousands of local anesthetic injections on a daily basis with few reports of serious complica tions, negative affects still occur. Local anesthetic complications are classified as ei ther local or systemic. Local complications include pain experience during administrati on, insufficient or excessive anesthesia, iatrogenic or self-inflicted tissue damage, pe rsistent sensitivity, skin blanching, tissue necrosis hematoma formation, and infection. Misdir ected needle placement may result in facial or nerve paralysis and trismus (muscle spasms) (Lustig and Zusman, 1999). Local opthalmic comp lications including Horner syndrome and vision loss also have been attributed to local anesthetics. However, these instances are rare and almost always transient. Between the years 1960 and 2005 only 39 cases of opthalmic complications resulting from dental anesthesia were published in English (Horowitz et al., 2005).

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53 Systemic complications are typically psychogenic in nature and occur less frequently than local complications (Madan et al., 2002). Emotional reactions to the administration of local anesthetia may result in vasovagal collapse or hyperventilation Trust in the dentist and fear-reducing treatment may prevent such effects (Baart and Brand, 2008). Local anesthetics may become toxi c if an improper dosage is given or if the patient undergoes an allergic reaction to the additives (Blanton and Jeske, 2003). Overall, the administration of local anes thetics is a safe and effective procedure with few side effects. Modern research rare ly reports complications and those that are covered typically last no longer than several hours. Fortunately, dentists can avoid most of these complications by employing th e proper anatomical and pharmocological measures taught in dental school. A we ll-trained dentist s hould prevent these complications by recognizing them at an ea rly stage and providing adequate treatment. Alternative Methods As is always the case in patient care, there are substitute methods available in dentistry that bypass the typical procedure in the dentist office. These methods are limited and include the use of acupunctu re, which was already addre ssed in chapter one as an alternative method to pain treatment, and implementing computer delivery systems, which have been proven to reduce injection pain that might be caused by human touch. Both of these methods have scientific back ing and should be considered when dealing with an especially anxious patient. Acupuncture

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54 It has only been in the last 25 years that acupuncture has gained attention from neurophysiological researchers, resulting in well-conducted clin ical trials and acceptance of the technique as a valuable tool for pain management. The current scientific understanding of acupuncture is that the insertion of a needle into an acupuncture point creates a small inflammatory process, signali ng the release of neurot ransmitters (such as bradykinin) and stimulating A fibers. These fibers inhibit the incoming painful sensation by releasing enkephalin (Rosted, 2000). The im plementation of acupuncture in dentistry is mostly seen with special cases and TMD patients. In general, dentists resort to acupuncture after they have exhausted all other therapeutic measures (Thayer, 2007). This author finds treating acupunctu re as a last resort to be unfair to both the patient and clinician. For the patient, acupuncture may enge nder false hopes of a miracle cure while this path may lead the clinic ian to abandonment of further study after rounds of repeated failure. Acupuncture is also used to supplement traditional treatments under special circumstances. Examples include implem enting acupuncture to suppress the gagging reflex during impression taking, to reduce the use of postoperative analgesics to drug sensitive patients, and controlling pre-opera tive anxiety. Acupuncture may also be used as an adjunct to, or replacem ent of, routine treatments fo r complex conditions such as facial pain or TMD. A dentist may on ly perform acupuncture after completing a postgraduate course (Rosted, 2000). There ar e no published works on its use in oral surgery or routine dental hygiene. Computerized delivery

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55 Low-pressure microprocessor-controlled delivery systems, known as computerized delivery system for intrasulcula r (CDS-IS) anesthesia, have been developed by Milestone Scientific to decrease the pressu re and speed of anesth etic injection. These products are the Single Tooth Anesthesia (STATM) System, which provides visual and aubible feedback on proper needle placement at the injection site, and CompueDent, which utilizes a SafetyWand (pen-like instru ment) to inject the local anesthetic in several regions of the mouth (Ashkenazi et al., 2005). Several articles have been published on the effectiveness of CDS, claiming that they decreases pain-disruptive behavior during palatal injections but have no effect on buccal infiltration or mandibular block (Ram and Peretz, 2003, Allen et al., 2002, Gibson et al., 2000). In conclusion, dental analgesics of all kinds are an important facet in successful dental treatment. Inhalation anesthetics are an effective measure for putting the patient at ease and remain one of the more enjoyable as pects of dental treatment. Dentists use intravenous sedation as a tool to eliminate procedur al pain but it requires a complex cocktail of drugs and may be risky if not performed by skilled professionals. Local anesthetics, which encompass the largest catego ry of dental analgesi cs, have been proven effective with few complications. Alternat ive methods are availa ble to special case patients and have also been reported to redu ce dental anxiety and pa in. Overall, dental analgesics have proven to be wo rth their weight in gold in th e dental office and continue to be a focus of modern dental research

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55 Conclusion A fully comprehensive analysis of pain transduction in the human body has yet to be established by scientific research. The investigative work put into this thesis has uncovered several gaps that support the form er conclusion. In this section the missing information will be re-examined and techniques on how to unfold these understudied areas will be postulated. This portion will also serve as a summary of the information presented in the introduc tion and body chapters. Information Gaps with Research Suggestions The introduction serves as a starting point for the eval uation of pain transmission by providing a historical bac kground of pain theory and an explanation of two major concepts, the gate control theory and the neur omatrix theory. A description of the genetic origins and psychological impact of pain is included to expand upon the notion that pain transmission is a highly indi vidual sensation. The end pages relate what the majority of the body covers, pain transductions in the or ofacial region and how/w hy dental analgesics are used to control such sensation. The first chapter serves as an overvie w of nociceptive transmission in the body. Here it is shown the classical nociceptive proj ection is the spinothala mocortical route but another ascending pathway projects from the spinal cord to the parabranchial nucleus, and then continues on to the hypothalamus and the amygdala (Kandel et al., 2000 and Rainville, 2002). However, there are lim ited amounts of information known of the descending modulation of nociceptive activ ity. Perhaps MRIs and PET scans may be

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56 used to better understand the be havior of pain signals after they have been processed by the brain. Assessment and management tools for both adults and children are also addressed in the first chapter. Assessment models vary from one-dimensional scales that express pain as a color or facial expression to lengthy questionnaires and multidimensional models. As with any assessment method, esp ecially when dealing with the complex sensation of pain, these techniques are subjec t to bias and receive heavy criticism from the scientific community. The clinical treatme nt of chronic pain resorts to the use of prescription anticonvulsants when necessary. The physiological process of how this treatment works remains unknown yet results prove it useful. Case studies involving anticonvulsant treatments are lacking as with ho listic measurements as well. Perhaps, if Western medication continues to embrace and explore non-clinical treatments this will become a nonissue. The second chapter covers the functiona l anatomy of the trigeminal nerve and nociception in the orofacial region along with the common co rresponding disorders. The chapter demonstrates that pain intensity is dependent upon the frequency of the sensory stimulation and the number of excited nerve fibers. Any stimulation in the orofacial region results in the propagation of primary A and C fibers, primarily in the trigeminal nerve. When the signal is transported to the ganglion, it synapses onto secondary fibers that run to the fifth brainstem neurosensory complex (Baart and Brand, 2006). From that point, they project to the thalamus and the cerebral cortex. The s econdary C fibers run through the thalamus, into the cerebral cort ex and project into the hypothalamus. The secondary A fibers terminate in the caudal nucleus, wh ere they activate tertiary tracts

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57 which run to other parts of the thalamus and somatosensory complex (Kandel et al., 2000). The second chapter also presents inform ation on the diagnosis, treatment, and mechanisms of several orofacial pain disorders. There is very little scientific explanation as the to origins/causation of these disord ers, proving diagnosis difficult. Information on reflex circuits and sensorimotor mechanisms of orofacial pain is lacking and warrants investigation. Rostral components of the VBSNC (polaris and interpolaris) remain unexplored while subnucleus caudalis hogs all the scientific attention. This occurs despite evidence that lesions on the upper components a ffect orofacial pain sensitivity. The same techniques used to explore caudalis should be performed on subnucleus interpolaris and polaris. Perhaps further investigation will prov ide insight into the causation of orofacial pain disorders and they will become less of an enigma. The final chapter focuses on dental analgesics and their role of inhibiting orofacial pain. Each category (inhalation, intravenous, and local) focuses on what is understood of the various chemicals, especially their mech anisms of action and chemical properties. Surprisingly, there is no scientific explanat ion on how inhalation anesthetics, such as nitrous oxide and sevoflurane, suppress the ce ntral nervous system and cause a sense of relaxation. Also, the systemic breakdown of propofol, a common sedative hypnotic, remains unexplained. This author was surprised to uncover these gaps because all of these drugs are extremely common in the de ntal setting yet vita l aspects of their physiological effects remain unknown. Perhaps some type of fluorescent demarcation could be applied to the drugs to better track their route of action in the body.

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58 Future of Pain Research According to Ronald Melzack Current understandings of pain aside, it is the future of pain research that keeps many scientists optimistic. One such scientis t, Ronald Melzack, published an editorial in 2008 in Pain Practice, the official journal of the Worl d Institute of Pain, entitled The future of pain. In the editori al he describes the clinical importance of the gate control theory and the neuromatrix theory of pain, tw o papers that he spearheaded. He describes the neuromatrix theory as follows: it connects the field of pain to exciting current research on the mechanisms in the brain that generate the experience of pain. Melzack then goes on to expand upon th ree reasons to be optimistic about the future of pain research and therapy. He believes the use of imaging techniques to study physiological events in the brain of human beings while they simultaneously report their subjective pain experience will greatly expand the scope of pain research and foresees improvement in this technique. Melzack also believes that an increase in knowledge of the spinal cord and human genetics will pave the pathway towards new th erapeutic treatments for chronic pain. With regards to the spinal cord, he wrote the sh ift to a top-down strate gy that begins with brain function and conscious experience will expand the field of pain research by incorporating the rapidly growing knowledge of cognitive neuroscience and the evolution of the brain. According to Melzack, as th e understanding of human genetics progresses, the known number of genes related to pain increases. Combined with current psychological research, the study of pain has br oadened and now incorporates research in epidemiology and medical genetics as well as sociological and cu ltural studies. This author agrees with Melzacks editorial and suggests that further investigation towards

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59 non-clinical treatment methods is also warra nted. Pain research would benefit from exploring nontraditional routes such as hypnosis and acupuncture instead of treating them as last resorts.

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60 Works Cited Al-Chaer, 1998. A Role for the Dorsal Column in Nociceptive Visceral Inpu t Into the Thalamus of Primates. Journal of neurophysiology. 79:3143. 1998; Allen, K.D., D. Kotil, R.E. Larzelere, S. Hutfless, and S. Beiraghi. 20 02. Comparison of a computerized anesthesia device with a traditional syringe in preschool children. Pediatr.Dent. 24:315-320. Aronoff, D.M. 2006. New insight s into the mechanism of action of acetaminophen: Its clinical pharmacologic characteristics reflect its inhibition of the two prostaglandin H2 synthases. Clinical pharmacology and therapeutics. 79:9. 2006; Baart, J.A., and H.S. Brand. 2008 Local anaesthesia in dentistry. Blackwell, Chichester, West Sussex; [Ames, Iowa]. Becker, D.E., and K.L. Reed 2006. Essentials of Local Anesthetic Pharmacology. Anesth.Prog. 53:98-109. Berde, B. 2008. Opioid Side E ffects--Mechanism-Based Therapy. New England Journal of Medicine, The. 358:2400. 2008; Bergdahl, 1999. Burning mouth syndrome: prevalence and associated factors. Journal of oral pathology medicine. 28:350. 1999; Blanton PL, Jeske AH, ADA Council on Scientific Affairs, and ADA Division of Science. 2003. The key to profound local anesthesia: neuroanatomy. Journal of the American Dental Association (1939). 134:75360. Blanton PL, Jeske AH, ADA Council on Scientific Affairs, and ADA Division of Science. 2003. Avoiding Complications in Local Anesthesia In duction: Anatomical Considerations. JOURNALAMERICAN DENTAL ASSOCIATION. 134:888-894. Boynes, S.G., A.L. Lemak, and J.M. Close. 2006. M ilieu in Dental School and Practice General Dentists' Evaluation of Anesthesia Sedation Education in U.S. Dental Schools. Journal of Dental Education. 70:1289. Bulloch, B., and M. Tenenbein. 2002. Validation of 2 Pain Scales for Use in the Pediatric Emergency Department. Pediatrics. 110:e33. Burchiel, K.J., and K.V. Slavin. 2000. On the Natural History of Trigeminal Neuralgia. Neurosurgery. 46:152. Cahana A, and Forster A. 2006. Muecanismes de la chronicisation de la douleur oro-faciale aiguue. Revue De Stomatologie Et De Chirurgie Maxillo-Faciale. 107:156-60. Chanpong, B.,. 2004. Assessing the need and demand for sedation or general anesthesia in dentistry a national survey of the Canadian population. Clark, M.S., and A.L. Brunick. 2003. Handbook of nitrous oxide and oxygen sedation. Mosby, St. Louis, Mo. Costigan, M. 2000. Pain : Molecular mechanisms. The journal of pain. 1:35. 2000;

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61 Cruccu, G., A. Biasiotta, S. Di Rezze, M. Fiorelli, F. Galeotti, P. Innocenti, E. M illefiorini, and A. Truini. 2007. P09. Trigeminal neuralgia in patients with multiple sclerosis: Quantitative MRI-neurophysiological correlations with a voxel-based 3D brainstem model. CLINICAL NEUROPHYSIOLOGY -SHANNON-. 118:2818-2819. Dargan, D. 2002. Acetaminophen poisoning: an update for the intensivist. Critical care. 6:108. 2002; De Boever JA, Carlsson GE, and Klineberg IJ. 2000. Ne ed for occlusal therapy and prosthodontic treatment in the management of temporomandibular disorders. Part I. Occlusal interferences and occlusal adjustment. Journal of Oral Rehabilitation. 27:367-79. De Holanda Vasconcellos R.J., Do Egito Vasconcelos B.C., and Genu P.R. 2008. Influence of local anesthethics with adrenalina 1:100.000 in basic vital constants during third molar surgery. Med.Oral Patol.Oral Cir.Bucal Medicina Oral, Patologia Oral y Cirugia Bucal. 13:E431-E437. Diatchenko L, Slade GD, Nackley AG, Bhalang K, Sigu rdsson A, Belfer I, Goldman D, Xu K, Shabalina SA, Shagin D, Max MB, Makarov SS, and Maixner W. 2005. Genetic basis for individual variations in pain perception and the development of a chronic pain condition. Hum.Mol.Genet. 14:135-43. Dickenson AH. 2002. Gate control theory of pain stands the test of time. Br.J.Anaesth. 88:755-7. Dionne, R., J.C. Phero, and D.E. Becker. 2002. Management of pain & anxiety in the dental office. Saunders, Philadelphia. Dionne, R.A. 2001. CLINICAL PHARMACOLOGY Comparing Efficacy and Safety of Four Intravenous Sedation Regimens in Dental Outpatients This collaborative, multicenter study evaluates regimens of intravenously administered sedative drugs in outpatients undergoing removal of impacted third molars. The Journal of the American Dental Association. 132:740. Dossey BM. 1998. Holistic modalities & healing moments. The American Journal of Nursing. 98:44-7. Dubner, R., and K. Ren. 2004. Brainstem Mechanisms of Persistent Pain Following Injury. Journal of Orofacial Pain. 18:299-305. Eckard, R., I. Johnson, and D. Chapman. 2006. Mode lling nitrous oxide abatement strategies in intensive pasture systems. International Congress Series. 1293:76-85. Eger, E.I. 2005. The pharmacology of inhaled anesthetics. SEMINARS IN ANESTHESIA PERIOPERATIVE MEDICINE AND PAIN. 24:89-100. Fillingim RB. 2003. The melanocortin-1 receptor gene mediates female-specific mechanisms of analgesia in mice and humans. Proc.Natl.Acad.Sci.U.S.A. 100:4867-72. Fillingim, R.B., and A. Unruh. 2002. Sex, Gende r, and Pain. Contemporary Psychology. 47:736. Gibson RS, Allen K, Hutfless S, and Beiraghi S. 2000 The Wand vs. traditional injection: a comparison of pain related behaviors. Pediatr.Dent. 22:.

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62 Gidal BE. 2006. New and emerging treatment options for neuropathic pain. The American Journal of Managed Care. 12:269-78. Greco, P.S., and F.M. Conti. 2008. Pain management : new research. Nova Biomedical Books, New York. Greene CS. 2001. The etiology of temporomandibular disorders: implications for treatment. Journal of Orofacial Pain. 15:93-105. Hiatt, J.L., and L.P. Gartner 2002. Textbook of head and neck anatomy. Lippincott Williams & Wilkins, Philadelphia, Pa. Higginson, I.J. 2002. Epidemiology of Pain. IK Crombie, PR Croft, SJ Linton, L LeResche, M Von Korff (eds). Seattle, WA: IAS Press, 199 9, pp.332. ISBN 0-931092-25-6. International Journal of Epidemiology. 31:506. Horowitz, J., Y. Almog, A. Wolf, G. Buckman, and O. Geyer. 2005. Ophthalmic Complications of Dental Anesthesia: Three New Cases. Journal of Neuro-Ophthalmology : Official Journal of the North American Neuro-Ophthalmology Society. 25:95. Husain, L. 2002. NSAID inhibition of GI cancer grow th: clinical implications and molecular mechanisms of action. The American journal of gastroenterology. 97:542. 2002; Ide, F., and K. Kusama. 2002. Adenomatoid odontoma. ORAL SURGERY ORAL MEDICINE ORAL PATHOLOGY ORAL RADIOLOGY AND ENDODONTICS. 94:149-150. Kandel, E.R., J.H. Schwartz, and T.M. Jessell. 2000. Principles of neural scie nce. McGraw-Hill, Health Professions Division, New York. Kapur, 2003. Oral and Craniofacial Pain: Diagnosis, Pathophysiology, and Treatment. International anesthesiology clinics. 41:115. 2003; Keefe FJ, Lefebvre JC, Egert JR, Affleck G, Sulliv an MJ, and Caldwell DS. 2000. The relationship of gender to pain, pain behavior, and disability in osteoarthritis patients: the role of catastrophizing. Pain. 87:325-34. Keefe, F.J., M.E. Rumble, C.D. Scipio, L.A. Giorda no, and L.M. Perri. 2004. Psychological aspects of persistent pain: current state of the science. JOURNAL OF PAIN. 5:195-211. Kieffer, K. 1999. Opioids: first lessons from knockout mice. Trends in Pharmacological Sciences. 20:19. 1999; Kim, H., J.K. Neubert, A. San Miguel, K. Xu, R.K. Krishnaraju, M.J. Iadarola, D. Goldman, and R.A. Dionne. 2004. Genetic influence on variability in human acute experimental pain sensitivity associated with gender, ethnicity and psychological temperament. Pain. 109:488. Klasser G.D., Fischer D.J., and Epstein J.B. 2008. Burning Mouth Syndrome: Recognition, Understanding, and Management. Oral Maxillofac. Surg. Clin. North Am. Oral and Maxillofacial Surgery Clinics of North America. 20:255-271.

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63 Koltzenburg, M., S.B. MacMahon, R. Melzack, and P.D. Wall. 2006. Wall and Melzack's textbook of pain. Elsevier, Churchill Livingstone, Philadelphia, Pa. Lahoud GY, and Averley PA. 2002. Comparison of sevoflurane and nitrous oxide mixture with nitrous oxide alone for inhalation conscious sedation in children having dental treatment: a randomised controlled trial. Anaesthesia. 57:446-50. Lahoud GY, Averley PA, and Hanlon MR. 2001. Sevoflurane inhalation conscious sedation for children having dental treatment. Anaesthesia. 56:476-80. Lai, T., C. Lin, S. Kok, P. Yang, Y. Kuo, W. Lan, and H. Chang. 2006. Evaluation of mandibular block using a standardized method. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology and Endodontics. 102:462. Leibing, E. 2002. Acupuncture treatment of chronic low-back pain -a randomized, blinded, placebocontrolled trial with 9-month follow-up. Pain. 96:189. 2002; Leitch J, and Macpherson A. 2007. Current state of sedation/analgesia care in dentistry. Current Opinion in Anaesthesiology. 20:384-7. Lewis, 2007. Management of neuropathic orofacial pain. Oral surgery, oral medicine, oral pathology, oral radiology and endodontics. 103:32. 2007; Liebgott, B. 2001. The anatomical basis of dentistry. Mosby, St. Louis. Lustig, J.P., and S.P. Zusman. 1999. RESEARCH Immediate Complications of Local Anesthetic Administered to 1,007 Consecutive Patients In this prospective study, the authors assess the immediate complications from administration of local anesthetic. The Journal of the American Dental Association. 130:496. Madan GA, Madan SG, and Madan AD. 2002. Failure of inferior alveolar nerve block: exploring the alternatives. Journal of the American Dental Association (1939). 133:843-6. Malamed SF, Gagnon S, and Leblanc D. 2000. Effi cacy of articaine: a new amide local anesthetic. Journal of the American Dental Association (1939). 131:635-42. Mann, E.M., and E.C.J. Carr. 2006. Pain mana gement. Blackwell Pub., Oxford; Malden, MA. Meldrum ML. 2003. A capsule history of pain management. JAMA : The Journal of the American Medical Association. 290:2470-5. Melzack R. 2008. The future of pain. Nat.Rev. Drug Discov.Nature Reviews Drug Discovery. 7:. Melzack R. 2001. Pain and the neuromatri x in the brain. J.Dent.Educ. 65:1378-82. Mogil JS, Wilson SG, Chesler EJ, Rankin AL, Nemmani KV, Lariviere WR, Groce MK, Wallace MR, Kaplan L, Staud R, Ness TJ, Glover TL, Stankova M, Mayorov A, Hruby VJ, Grisel JE, and Mogil JS. 1999. The genetic mediation of individual differences in sensitivity to pain and its inhibition. Proc.Natl.Acad.Sci.U.S.A. 96:7744-51.

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64 Moore, K.L., A.F. Dalley, and A.M. R. Agur. 2006. Clinically oriented anatomy. Lippincott Williams & Wilkins, Baltimore, MD. Morrison SF, Nakamura K, and Madden CJ. 2008. Central control of thermogenesis in mammals. Experimental Physiology. 93:773-97. Mostofsky, D.I., A.G. Forgione, and D.B. Giddon 2006. Behavioral dentistry. Blackwell Pub., Ames, Iowa. Nagasako EM, Oaklander AL, and Dworkin RH. 2003. Congenital insensitivity to pain: an update. Pain. 101:213-9. Peyron, R. 2000. Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiologie clinique. 30:263. 2000; Price DD. 2000. Psychological and ne ural mechanisms of the affective dimension of pain. Science (New York, N.Y.). 288:1769-72. Procacci P, and Maresca M. 1994. Descar tes' physiology of pain. Pain. 58:. Rainville, J. 2002. Brain mechanisms of pain affect and pain modulation. Current Opinion in Neurobiology. 12:195. 2002; Ram, D., and B. Peretz. 2003. The Assessment of Pain Sensation During Local Anesthesia Using a Computerized Local Anesthesia (W and) and a Conventional Syringe. ASDC J.Dent.Child. 70:130-133. Rein, T. 2004. A herbal remedy, Hyben Vital (stand. powder of a subspecies of Rosa canina fruits), reduces pain and improves general wellbeing in patients with osteoarthritisa double-blind, placebo-controlled, randomised trial. Phytomedicine. 11:383. 2004; Rhodes, D. 2006. Hypnosis and the Remediation of Pain. BA thesis (New College of Florida). 40-42, 49 Riker, R.R., Y. Shehabi, P.M. Bokesch, D. Ceraso, W. Wisemandle, F. Koura, P. Whitten, B.D. Margolis, D.W. Byrne, E.W. Ely, and M.G. Rocha. 2009. Dexm edetomidine vs Midazolam for Sedation of Critically Ill Patients: A Randomized Trial. JAMA : The Journal of the American Medical Association. 301:489. Rosted, P. 2000. Introduction to acupuncture in dentistry Current research concludes that acupuncture could supplement conventional treatment modalities. British Dental Journal. 189:136-142. Royer, R., and C. Paarmann. 2007. Pain control fo r dental practitioners : an interactive approach. Lippincott Williams & Wilkins, Baltimore. Sessle BJ. 2005. Peripheral and central mechanisms of orofacial pain and thei r clinical correlates. Minerva Anestesiologica. 71:117-36. Sessle, B.J. 2000. Acute and Chronic Craniofaci al Pain: Brainstem Mechanisms of Nociceptive Transmission and Neuroplasticity, and Their Clinical Correlates. Critical Reviews in Oral Biology & Medicine. 11:57-91.

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65 Stegenga B, and Lobbezoo F. 2000. Bruxism in temporomandibular disorders. Netherlands Journal of Orofacial Sensation. 107:285-8. Steinmeyer, J. 2000. Pharmacological basis for the therapy of pain and inflammation with nonsteroidal anti-inflammatory drugs. Arthritis Res. 2:379-385. Strunin, L. 2007. Intravenous conscious sedation for dental treatment: am I my brother's keeper? ANAESTHESIA -LONDON-. 62:645-647. Sutton, A.L. 2003. Dental care and oral health sourcebook Omnigraphics, Detroit, MI. Svensson, P., and T. Graven-Nielsen. 2001. Topical Review: Craniofacial Muscle Pain: Review of Mechanisms and Clinical Manifestations. Journal of Orofacial Pain. 15:117-145. Thayer, M.L.T. 2007. The Use of Acupuncture in Dentistry. Dental Update. 34:244-250. Turk DC, and Okifuji A. 2002. Psychological factors in chronic pain: evolution and revolution. J.Consult.Clin.Psychol. 70:678-90. Ustun, Y., M. Gunduz, Erdogan, and M.E. Benlidayi. 2006. Dexmedetomidine Versus Midazolam in Outpatient Third Molar Surgery. Journal of Oral and Maxillofacial Surgery : Official Journal of the American Association of Oral and Maxillofacial Surgeons. 64:1353. Vertosick, F.T. 2000. Why we hurt : the natural history of pain. Harcourt, New York. Warren, M.P., and J.L. Fried. 2001. Temporomandibular Disorders and Hormones in Women. CELLS TISSUES ORGANS. 169:187-192. Zukrzewska, J.M., H. Forssell, and A.M. Glenny. 2004. REVIEWS AND ABSTRACTS Interventions for the treatment of burning mouth syndrome: A systematic review. American Journal of Orthodontics and Dentofacial Orthopedics. 125:400. Zvartau-Hind M, Din MU, Gilani A, Lisak RP, and Khan OA. 2000. Topiramate relieves refractory trigeminal neuralgia in MS patients. Neurology. 55:1587-8.

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66 Picture Appendix Figure 1: Illustration of The Gate Control Theory of Pain put forth by Wall and Melzack in 1965. The gate control theory proposes th at the substantia gelatinosa is the main control site. The control mechan ism is referred to as a 'gate' and is operated by external and internal influences. Pain impulses can onl y pass through when th e gate is open, and not when it is closed (Dickenson, 2002). graphic taken from www.paintechnology.com

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67 Figure 2: Illustration of the inne rvations of the trigeminal nerv e. The largest of the cranial nerves, it serves both sensory and moto r function in the face (Liebgott, 2001). graphic taken from www.doctorspiller.com

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68 Figure 3: Graphic interpretation and cross sec tion of the fifth brainstem nuclear complex (VBSNC). Subnucleus caudalis has received th e most attention from the scientific communitry but attention is star ting to shift to oralis and interpolaris. Animal studies show that a lesion on any portion of the VB SNC results in the di sruption of facial innervation (Sessle, 2000). Image taken from http://thalamus.wustl.edu/course/face.html

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69 Figure 4: Table diagram of the biopsychosocial model of pain. The philosophy behind this model is that there is a symbiotic relationship between the body and the mind. It was the first of its kind to take all three influen ces (biological, psychological, and social) into account when diagnosing pain (Lewish et al., 2007). taken from www.continuingedcourses.net

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70 Glossary All definitions taken directly from the thes is* or Mosbys dictionary of medicine, nursing and health professionals, 7th Edition, 2006, unless otherwise noted. Abate: To decrease or redu ce in severity or degree Acetaminophen: An analgesic drug used in many nonprescription pain relievers Action potential: An electrical impulse cons isting of a self-propagating series of polarizations and depolarizations, transmitte d across the plasma membranes of a nerve fiber during the transmission of a nerve impul se and across the plasma membranes of a muscle cell during contr action or other activity. Acupuncture: A traditional Chinese method of producing analgesia or altering the function of a body system by inserting fine, wire -thin needles into th e skin at specific sites on the body along a seri es of lines, or chan nels, called meridians. Acute pain: Pain that comes on quickly, can be severe, but lasts a relatively short time. (www.medicinenet.com) Adrenaline: See epinephrine Allergen: An environmental substance that can produce a hypersensiti ve allergic reaction in the body but may not be intrinsically harmful. Alveolar membrane: Any of the membranes of the maxilla through which blood vessels and the nerves of the upper teeth pass. Amide: A chemical compound formed from an organic acid by the substitution of an amino group for the hydroxyl or a carboxyl group. Or, a chemical compound formed by the deprotonation of ammonia, or a primary or secondary amine. Amino alcohol: Any chemical containing a hydroxyl group and the monovalent radical NH2. Amino-: Prefix for a chemical name indicated by the monovalent radical NH2. Amygdala: An almond-shaped mass of gray matter in the front portion of the temporal lobe of the brain. Analgesic: Relieving pain Antagonist: Any agent, such as a drug or musc le, that exerts an opposite action to that of another or competes for the same receptor site. Anterior: The front of a structure. Antidiuretic: Pertaining to the blocking of the effects of impulses transmitted by the adrenergic postganglionic fibers of the sympathetic nervous system.

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71 Antithesis: The rhetorical contrast of ideas by means of parallel arrangements of words, clauses, or sentences. (www.merriam-webster.com/dictionary) Arachidonic acid: A long chain fatty acid that is a component of lecithin and a basic material in the biosynthesi s of some prostoglandins. Aromatic: Pertaing to organic chemical structures including a 6-carbon ring. Articular cartilage: A type of connective ti ssue that covers the ar ticulating surfaces of bones with synovial joints. Articular disk: The platelike, cartilagenious end of certain bones in movable joints, sometimes closely associated with surrounding muscles or with cartilage. Ascending: A nervous system pathway th at carries impulses toward the brain. Axon: An extension, usually long and slende r, of a neuron capable of conducting action potentials or self-propagating nervous impulses. A fiber*: Small diameter, thinly myelinated nerve fibers that conduct signals around 530 m/s. Base: A chemical compound that increases the concentration of hydroxide ions in aqueous solution. Benzene ring: A hydrocarbon (C6H6) in ring form with alternating double bonds. Bilateral: Having two sides. Bisulphate: A compound contai ning two sulphate groups. Brainstem: The portion of the brain compri sing the medulla oblongata, the pons, and the mesencephalon. Bruxism: The compulsive, unconscious grinding or clenching of the teeth, especially during sleep. Buccal: Towards the cheek C fiber*: Nerve fiber with a small diamet er and no myelination. They conduct action potentials slowly (less than 1.0 m/s) when compared to other fibers. c-Fos protein: Cellular DNAbinding protein encoded by the c-fos genes. They are involved in growth-related transcript ional control. (www.medicalnet.com) Candida: A genus of yeast like fungi. Catecholamine-O-methyltransferase: An enzy me that deactivates the catecholamines dopa, dopamine, epinephrine, and norepinephrine.

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72 Catecholamine: Any one of a group of com pounds composed of a cat echol molecule and the apliphatic portion of an amine. Some are produced by the body and function as key neurological chemicals. Cation: A positively charged ion. Caudal: Signifying a position towards the distal end of the body, or an inferior position. Cavity excavation: The hollowing out of a hole within a larger structure. Cell membrane: The outer covering of a ce ll, often having projecting microvilli and containing the cellular cytoplasm Cell: The fundamental unit of all living tissue. Central nervous system: One of the two main divisions of the nervous system, consisting of the brain and the spinal cord. Cerebral: Suffix referring to the brain. Cerebrovascular: Pertaining to the vascul ar system and blood supply to the brain. Chondrotin sulphate: A sulfated glycosaminogl ycan composed of a chain of alternating sugars. It is usually found attached to proteins as part of a proteoglycan. Chronic pain*: Pain that continues or r ecurs over a prolonged period, caused by various diseases or abnormal conditions Cingulate: Having a zone or a girdle, usually with transverse markings. Cognitive: Pertaining to the mental processe s of comprehension, judgment, memory, and reasoning, as contrasted with emotional and volitional processed. Conduction: The process by which a nerve impulse is transmitted. Congenital: Present at birth. Conjugation: An exchange or transfer of ge netic information between two individuals in certain types of unicellular organisms, including bacteria and some protozoa. Cortex: The outer layer of a body structure or organ. Cortic-: Combining form m eaning cortex or bark. Corticosteroid: Any one of hor mones elaborated by the adrenal cortex that influence or control key processes of the body. Cutaneous: Pertaining to the skin Cytochrome P450: A protein involved with m itochondrial electron tran sport in the liver and during drug detoxification

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73 Cytochrome P4502D6: See cytochrome P450 Cytoplasm: All of the substa nce of a cell other than th e nucleus and the cell wall. Delirium: A state of frenzied excitement or wild enthusiasm. An acute organic mental disorder characterized by confusion, diso rientation, restlessne ss, clouding of the consciousness, incoherence, fear, anxiety, excitement, and often by illusions. Depolarization: The reduction of a membra ne potential to a less negative value. Descending: A nervous system pathway that carries impulses away from the brain. Devils claw: An herb, Harpagophytum procumbens native to southern Africa. Dexmedetomidine: A sedative agent. Diffusion: The process in which particles in a fluid move from an area of higher concentration to an area of lo wer concentration, resulting in an even distribution of the particles in the fluid. Diphenhydramine: An antihistamine. Distal: Away from or the farthest from a point of origin or attachment. Dopamine: A naturally occurring sympathetic nervous system neurotransmitter that is the precursor of norepinephrine. Dorsal: Suffix meaning the back. Electrodermal: Pertaining to electrical pr operties of the skin, particularly altered resistance. Electromyographic: A technique for evaluating and recording the activation signal of muscles. (www.medicalnet.com) Enamel: The outer covering of teeth. Endocrine: Pertaining to a process in which a group of cells secrete into the blood or lymph circulation a substance that has a specifi c effect on tissues in another part of the body. Endodontic: Relating to the dental pul p, tooth root, and surrounding tissues. Endogenous: Growing within the body. Enkephalin: One of two pa in-reliving pentopeptides produced in the body. Enzyme: A complex produced by living cells that catalyzes chemical reactions in organic matter. Epinephrine: An endogenous adrenal horm one and synthetic adrenergic agent.

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74 Equilibrium: A state of balance or rest resu lting from the equal action of opposing forces such as calcium and phosphorus in the body. Ester: A class of chemical compounds form ed by the bonding of an alcohol and one or more organic acids. Estrogen: One of a group of hormonal steroi d compounds that promote the development of female secondary sex characteristics. Etiology: The study of all factor s that may be involved in th e development of a disease. Face scale*: Pain measurement technique in which faces are used to express various amounts of pain. Felypressin*: A synthetic chemi cal derived from vasopressin Forebrain: The anterior primitive cerebral vesicle which further divides into the diencephalon and telencephalon. Frontal lobe: The largest of five lobes consti tuting each of the two cerebral hemispheres. Gamma-aminobutyric acid (GABA): An amino acid that functions as an inhibitory neurotransmitter in the brain and spinal cord. Ganglion: A knot or knotlike mass of nervous tissue Glucosamine: An amino sugar that acts as a precursor in the bioc hemical synthesis of glycosylated proteins and lipids. Glycoprotein: Any of the large group on conjugated proteins in which the nonprotein substance is a carbohydrate. Haplotype: A combination of alleles at multiple loci that are transmitted together on the same chromosome. Hematoma: A collection of blood trapped in th e tissues of the skin or in an organ, resulting from trauma or incomplete hemostasis after surgery. Hemoglobin: A complex protein-iron compound in the blood that carries oxygen to the cells from the lungs and carbon dioxide away from the cells to the lungs. Hemorrhage: A loss of a large amount of blood in a short period, eith er externally or internally. Hormone: A complex chemical substance produced in one part or organ of the body that initiates or regulates the ac tivity of an organ or a group of cells in another part. Horner syndrome: A neurological condition characterized by miotic pupils, ptosis, and facial anhidrosis, which results from a lesion in the spinal cord, with damage to a cervical nerve or any ascending part of the sympathetic outflow to the face/head.

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75 Hyben vital*: A standardized dry powder made from Rosa canina Hydrochrolic acid: An aqueous solution of hydrogen chloride or hydrogen ions and chloride ions. Hydrophilic: Pertaining to the property of a ttracting or associating preferentially with water molecules, possessed by polar radicals or ions. Hyperventilation: When the pulmonary vent ilation rate is greater than what is metabolically necessary for gas exchange. Hypnosis: A passive, trancelike state that resembles normal sleep during which perception and memory are alte red, resulting in increased responsiveness to suggestion. Hypothalamus: A portion of the diencephalon of the brain, forming the floor and part of the lateral wall of the third ventricle. Iatrogenic: Caused by treatment or diagnosis procedures. Idiopathic: Without a known cause. Immune: Being protective agains t infective or allergic diseases by a system of antibody molecules and related resistance factors. Immunocytochemical: The branch of immunoche mistry dealing with cells and cellular activity. Infiltration: The process whereby a fluid passes into the tissues. Insula: Island or island-shaped Interstitial fluid: Liquid pertaining to the space between cells or organs. Intra-: Prefix meaning situated, formed, or occurring within. Intravenous sedation: Achieving sedation by injection drugs into a vein. Ion: A charged particle Ipsilateral: Affecting th e same side of the body. Lamina: Any thin, flat layer of membrane or other bulkier tissue. It may be structureless or a part of a structure. Lateral: Pertaining to the side. Lemniscal system: A part of the somatosensory network of large diameter myelinated A fibers. Limbic system: A group of structures within the rhinencephalon of the brain that are associated with various emotions and feeli ngs such as anger, fear, sexual arousal, pleasure, and sadness.

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76 Lipid bilayer: A thin membrane made of two layers of lipid molecules. Lipophilic: A tendency to at tract or absorb fat. Malocclusion: Abnormal contact between the teeth of the upper jaw and those of the lower jaw. Mastication: Chewing, tearing, or grinding f ood with the teeth while it becomes mixed with saliva. Mechanical nociceptors*: A class of nociceptors that activate when an intense pressure is applied to the epidermis. They are composed of A fibers. Meckels cave: Houses the trigemin al ganglion (gasserian ganglion). Medial: Pertaining to, situat ed in, or oriented toward the midline of the body. Meditation: A state of consci ousness in which the individu al eliminates environmental stimuli from awareness so that the mind has a single focus, producing a state of relaxation and relief from stress. Medulla: The most internal part of a structure. Melanocortin-1: Key protein for ha ir and skin color regulation. Metabolite: A substance produced by metabolic action or necessary for a metabolic process. Methyl: the chemical radical CH3. Minimum alveolar concentration*: A concept used to compare the strengths of anesthetic compounds. Mucosa: Relating to the mucous membrane. Musculoskeletal: Pertaining to the muscles and skeleton. N-methyl-D-aspartate (NMDA): An amino acid derivative acting as a specific agonist at the NMDA receptor, and therefore mimics the action of the neurotransmitter glutamate on that receptor. Narcotic: Pertaining to a substance th at produces insensibility or stupor. Necrosis: Localized tissue deat h that occurs in groups of ce lls in response to disease or injury. Neoplastic anomaly: An abnormal growth of new tissue, benign or malignant. Nerve: One or more bundles or impulse-carrying fibers, mye linated or unmyelinated or both, that connect the brain and the spin al cord with other parts of the body.

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77 Neuralgia*: An abnormal condition characte rized by severe stabbing pain, caused by a variety of disorders aff ecting the nervous system. Neuroanatomic: Relating to the st ructure of the nervous system. Neurobiology: Branch of biology that is c oncerned with the anatomy and physiology of the nervous system. Neuroendocrine: Pertaining to or resembling the effects pr oduced by endocrine glands strongly linked with the nervous system. Neurohormone: A hormone produced in neuros ecretory cells such as those of the hypothalamus and released into the bloodstream, the cerebrospinal fluid, or intercellular spaces of the nervous system. Neurokinin: A mammalian deca-peptide tachyki nin found in the central nervous system. (www.medicalnet.com) Neuromatrix*: A widespread network of neur ons that consists of loops between the thalamus and cortex as well as between the cortex and limbic system which acts as the anatomical substrate of the body-self. Neuromodules*: Subsections of the neuromatrix. Neuron: The basic nerve cell of the nervous sy stem, containing a nucleus within a cell body and extending one or more processes. Neuropathic*: Inflammation or degene ration of the peripheral nerves. Neurosignature*: Pattern create d by the repeated cyclic proc essing and synthesis of nerve impulses through the neuromatrix. Nociceptive: Pertaining to a neural receptor for painful stimuli. Non-steroidal anti-inflammatory drug (NSAID): Any of a group of drugs having analgesic and anti-inflammatory effects. Norepinephrine: An adrenergic hormone (c atecholamine) that acts to increase blood pressure by vasoconstriction but does not affect cardiac output. Nucleus: A group of nerve cells of the centr al nervous system having a common function. Opiate: An opioid drug that co ntains opium, derivatives of opium, or any of several semisynthetic or synthetic dr ugs with opium-like activity. Oxidation: Any process in which the oxygen cont ent or the number of bonds to oxygen in a compound is increased. Pain*: An unpleasant sensation caused by noxi ous stimulation of the sensory nerve endings.

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78 Palatal: Pertaining to the palate or palate bone. Panoramic radiograph: An x-ray image of a curved body surface, such as the upper and lower jaws, on a single film. Para amino benzoic acid (PABA): A substa nce often associated with the vitamin B complex. It is a sulfonamide antagonist. Parabranchial nucleus: A region in the human brain that is related to the ascending reticular activating system. (www.medicalnet.com) Paresthesia: Any subjective sensation, expe rienced as numbness, tin gling, or a pins and needles feeling. Paroxysm: A marked, usually ep isodic increase in symptoms Pathogenesis: The source of cause of an illness or abnormal condition. Pathophysiology: The study of the biologic and phys ical manifestations of disease as they correlate with the underlying abnormali ties and physiologic disturbances. Percussion*: A technique in physical examin ation of tapping the body with fingertips or fist to evaluate the size, borde rs, and consistency of some of the internal organs and to discover the presence and evaluate the amount of fluid in a body cavity. Periacqueductal gray: The midbrain grey ma tter that is locate d around the cerebral aqueduct within the midbrain. (www.medicalnet.com) Periodontal: Pertaining to the suppor ting structures of a tooth. Peripheral nervous system: The motor and sens ory nerves and ganglia outside the brain and spinal cord. Peripheral: Pertaining to th e outside, surface, or surrounding area of an organ, other structure, or fi eld of vision. Persistent pain*: Subdivided into two categories, nociceptive and neuropathic. Nociceptive pains are the result of the direct activation of nociceptors that are found in the skin or soft tissue. This activation is seen as a response to tissue injury from an identifiable source/reason a nd usually arises from inflam mation. Neuropathic pains result from a blunt injury to nerves in the peripheral or central nervous systems. pH: A scale representing the re lative acidity of a solution. Phospholipase A2: Cleaves an SN2 acyl chain. Phospholipid: A phosphorus-containing lipid. Polymodal nociceptors*: Nerve fibers w ith a small diameter and no myelination.

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79 Pons: A prominence on the ventral surface of the brainstem, between medulla oblongata and the cerebral peduncles of the midbrain. Positron emission tomography*: A nuclear medi cine imaging technique which produces a 3D image or picture of f unctional processes in the body. Posterior: In the back part of a structure, such as of th e dorsal surface of the human body. Preauricular: Located anterior to the auricle of the ear. Preservative: A substance added to a produc t to destroy or inhibit multiplication or microorganisms. Prodromal: Pertaining to early symptoms that may mark the onset of a disease Prophylactic: An agent that prev ents the spread of disease Prostaglandin*: One of several potent unsaturat ed fatty acids that act in exceedingly low concentrations on local target organs. They are produced in small amounts and have a large array of significant effects, including a role in inflammation. Proximo-: Combining form meaning near or opposite of distal, cen tral, or a point of attachment Pseudo cholinesterase: An enzyme that ac ts as a catalyst in the hydrolysis of acetylcholine to choline and acetate. Psychogenic: Origina ting within the mind Psychosocial: Pertaining to a combinati on of psychological and social factors Qi Gong: A form of Chinese exercise stimula tion therapy that proposes to improve health by redirecting mental focus, breathing, coordination, and relaxation. The goal is to rebalance the bodys own healing capacities by activating proposed electrical or energetic currents that flow along meridians throughout the body. Receptive field: The active area of a nociceptor. Rheumatoid arthritis: A chr onic, inflammatory, destructiv e, and sometimes deforming collagen disease that has an autoimmune component. Root canal: A material is placed in the pulp canal of a tooth to seal the space previously occupied by the dental pulp. Root ganglia: See ganglion Rostral: beak-shaped S-adenosylmethionine: A coenzyme i nvolved in methyl group transfers.

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80 Sentinent neural hub*: areas of the brain (dubbed the sentinen t neural hub) in which the stream of nerve impulses converts into a st ream of awareness th at is continually changing. Serine palmitoyltransferase: An enzyme. Serotonin: A naturally occurr ing derivitaive of tryptophan f ound in platelets and in cells of the brain and the intestine. It acts as a potent vasoconstrictor and neurotransmitter. Silent nociceptors*: Type of nocicepor found in the internal organs located in the main cavity of the body (viscera) but typically are not activated by noxious stimulation. However, for unknown reasons their firing threshold is drama tically reduced by inflammation and various chemical insults Single nucleotide polymorphism : A genetic polymorphism between two genomes that is based on deletion, insertion, or exchange of a single nucleotide. Solubility: The maximum amount of a solute th at can dissolve in a sp ecific solvent under a given set of conditions. Somato-: Combining form meaning body. Somatosensory system: The components of the central and peripheral nervous systems that receive and interpret sensory informati on from organs in the joints, ligaments, muscles, and skin. This system processes in formation about the length, degree of stretch, tension, and contraction of muscles, pain, temperature, pressure, and joint position. Somatotopical arrangement: The maintenance of spatial organization within the central nervous system. Soybean unsaponifiable: Compound extracted from soybean oils; believed to affect the development and repair of cartilage that protects the ends of the bones Spinothalamocortical route: Traveling from the spinal cord to the cortex of the thalamus. Spinothalamic tract: Traveling from the spin al cord to the thalamus of the brain. Subcortical: Located below the cortex. Subcutaneous: Below the skin Substance P: A polypeptide neurotransmitter that stimulates vasodilation and contraction of intestinal and other smooth muscles. It also plays a part in pain sensation and salivary secretion. Superior: Situated above or orie nted toward a higher place. Synapse: The region surround th e point of contact between two neurons or between a neuron and an effector organ, across whic h nerve impulses are transmitted through the action of a neurotransmitter.

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81 Synaptic transmission: The passage of a neur al impulse across a synapse from one nerve fiber to another by means of a neurotransmitter. Testosterone: A naturally o ccurring androgenic hormone Thalamus: One of a pair of large oval ne rvous structures made of gray matter and forming most of the lateral walls of the th ird ventricle of the brain and part of the diencephalon. It relays sensory information, excluding smell, to the cerebral cortex. Thermal nociceptors*: Nociceptors activated by extreme temperatures. Thiophene*: A Heterocyclic compound with the formula C4H4S. Toluidine*: Aryl amine whose chemical stru ctures are similar to aniline except that a methyl group is substituted onto the aromatic ring Tooth pulp: The center of a tooth made up of living soft tissue and odontoblasts. Topical: Pertaining to a drug or treatm ent applied to the surface of the body. Tricyclic antidepressants: Any of a group of antidepressant dr ugs that contain three fused rings in their chemical struct ure and that potentiate the ac tion of catecholamines; they rapidly block the reuptake of neurotransmitters. Trigeminal ganglia: A sensory ganglion of the trigeminal nerve that occupies Meckel's cave in the dura mater, covering the trigemin al impression near the apex of the petrous part of the temporal bone. (www.wikipedia.org) Trigeminal nerve*: Either of the largest pair of cranial nerves, essential for the act of chewing, general sensibility of the face, and mu scular sensibility of the obliquus superior. Trismus*: A prolonged spasm of the muscles of the jaw. Tyrosine kinase: An enzyme that can transf er a phosphate group from ATP to a tyrosine residue in a protein. Unilateral: Involving only one side. Vascularization: The process by which the body tissue develops prolif erating capillaries. Vasoconstrictor: Pertaining to a process, condition, or substance that causes the constriction of blood vessels. Vasodialation: An increase in the diameter of a blood vessel. It is caused by a relaxation of the smooth muscles in the vessel wall. Vasopression*: A hormone that decreases the production of urine by increasing the reabsorption of water by the renal tubules. Vasovagal: Pertaining to the vagus nerve. Ventral: Suffix meaning of th e stomach or abdominal region.

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82 Viscera*: The internal organs enclosed within a body cavity. Xylidine*: Any of the six isomers of xyl ene amine, or any mixture of them. linolenic acid: A non-essential polyuns aturated fatty acid which has some pharmacological actions. Found in oils from the seeds of evening primrose, borage, and blackcurrant. (www.medicalnet.com)