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Effects of High Dose Capsaicin on Facial Pain Perception

Permanent Link: http://ufdc.ufl.edu/UFE0024419/00001

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Title: Effects of High Dose Capsaicin on Facial Pain Perception
Physical Description: 1 online resource (33 p.)
Language: english
Creator: Campbell, Benjamin
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2009

Subjects

Subjects / Keywords: Dentistry -- Dissertations, Academic -- UF
Genre: Dental Sciences thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: A significant number of individuals suffer chronic pain associated with temporomandibular joint disorders (TMD); however, there still remain questions regarding the underlying pain mechanisms associated with TMD and therefore treatment strategies can be unclear. The transient receptor potential channel, vanilloid subfamily member 1 (TRPV1) has been identified as a target for pain control as it is expressed primarily on pain neurons and is involved with mediating inflammatory pain. Capsaicin, aTRPV1 agonist both activates and inactivates TRPV1-expressing neurons without producing tissue damage. A double-blinded, placebo-controlled clinical trial was used to investigate two specific aims: (1) To evaluate if chronic TMD patients modulate pain differently than normal control subjects; (2) To evaluate the analgesic efficacy of capsaicin in chronic TMD patients. Our results indicate that capsaicin significantly increases experimental pain in both TMD and non-TMD groups as compared to vehicle in the short term but shows a decrease of TMD pain in the week following . It has no effect on pressure pain threshold but it does decrease thermal pain threshold two hours after application though not one week out.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Benjamin Campbell.
Thesis: Thesis (M.S.)--University of Florida, 2009.
Local: Adviser: Neubert, John K.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2011-05-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2009
System ID: UFE0024419:00001

Permanent Link: http://ufdc.ufl.edu/UFE0024419/00001

Material Information

Title: Effects of High Dose Capsaicin on Facial Pain Perception
Physical Description: 1 online resource (33 p.)
Language: english
Creator: Campbell, Benjamin
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2009

Subjects

Subjects / Keywords: Dentistry -- Dissertations, Academic -- UF
Genre: Dental Sciences thesis, M.S.
bibliography   ( marcgt )
theses   ( marcgt )
government publication (state, provincial, terriorial, dependent)   ( marcgt )
born-digital   ( sobekcm )
Electronic Thesis or Dissertation

Notes

Abstract: A significant number of individuals suffer chronic pain associated with temporomandibular joint disorders (TMD); however, there still remain questions regarding the underlying pain mechanisms associated with TMD and therefore treatment strategies can be unclear. The transient receptor potential channel, vanilloid subfamily member 1 (TRPV1) has been identified as a target for pain control as it is expressed primarily on pain neurons and is involved with mediating inflammatory pain. Capsaicin, aTRPV1 agonist both activates and inactivates TRPV1-expressing neurons without producing tissue damage. A double-blinded, placebo-controlled clinical trial was used to investigate two specific aims: (1) To evaluate if chronic TMD patients modulate pain differently than normal control subjects; (2) To evaluate the analgesic efficacy of capsaicin in chronic TMD patients. Our results indicate that capsaicin significantly increases experimental pain in both TMD and non-TMD groups as compared to vehicle in the short term but shows a decrease of TMD pain in the week following . It has no effect on pressure pain threshold but it does decrease thermal pain threshold two hours after application though not one week out.
General Note: In the series University of Florida Digital Collections.
General Note: Includes vita.
Bibliography: Includes bibliographical references.
Source of Description: Description based on online resource; title from PDF title page.
Source of Description: This bibliographic record is available under the Creative Commons CC0 public domain dedication. The University of Florida Libraries, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.
Statement of Responsibility: by Benjamin Campbell.
Thesis: Thesis (M.S.)--University of Florida, 2009.
Local: Adviser: Neubert, John K.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2011-05-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2009
System ID: UFE0024419:00001


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1 EFFECTS OF HIGH DOSE CAPSAICIN ON FACIAL PAIN PERCEPTION By BENJAMIN K. CAMPBELL A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLOR IDA IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2009

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2 2009 Benjamin K. Campbell

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3 This is dedicated to my wife, my parents, and my children, who have reaffirmed Gods love and our (mans) purpose in life.

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4 ACKNOWLEDGMENTS I thank m y wife, Dana, for raising our children (the most important work in this life) while I have been in school, and my parents, Brent and Ronella Campbell, w ho have imparted their time, talents, and most importantly knowledge to me. I am indebted also to all of my professors from my first alma mater at Weber State Univer sity who unknowingly generated much interest in science and medicine; to those at my dental school alma mater, Virginia Commonwealth University; and especially my professors at Univ ersity of Floridas Department of Orthodontics, Doctors Timothy Wheeler, Calogero Dolce and Leandra Dopazo. I also want to acknowledge the influence the jobs I worked at after high sc hool had on me. I soon realized how dead end they were and they became the main impetus to acquire more knowledge. Lastly, I am indebted to and want to thank the following for their help in carrying out my research: John Neubert, D.D.S., Ph.D.; Roger Fillingim, Ph .D.; Chi Huynh, D.D.S.; Stephani e Fulger; Danielle Case; Ajay Kapedia D.D.S.; Mirta Basha; Dale Benjamin; Marie Taylor; and Rose Bittong.

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5 TABLE OF CONTENTS page ACKNOWLEDGMENTS ............................................................................................................... 4LIST OF TABLES ...........................................................................................................................7LIST OF FIGURES .........................................................................................................................8ABSTRACT ...................................................................................................................... ...............9 CHAP TER 1 INTRODUCTION .................................................................................................................. 10Background .................................................................................................................... .........10Capsaicin and the Vanilloid Receptor TRPV1 ................................................................ 10Capsaicin Utility ............................................................................................................. .11Significance .................................................................................................................. ...11Hypothesis and Specific Aims ................................................................................................ 122 METHODS ....................................................................................................................... ......13Subject Recruitment and Randomization ............................................................................... 13Inclusion Criteria .............................................................................................................13Exclusion Criteria ............................................................................................................14General ............................................................................................................................14Quantitative Sensory Testing ..................................................................................................14Pressure Pain ...................................................................................................................15Thermal Testing ...............................................................................................................15Drug Application .............................................................................................................16Measures ...................................................................................................................... ....173 RESULTS ....................................................................................................................... ........18Demographics .................................................................................................................. 18Experimental and Global Pain ......................................................................................... 18Thermal Pain Threshold ..................................................................................................19Pressure Pain Threshold ..................................................................................................204 DISCUSSION .................................................................................................................... .....275 CONCLUSIONS ................................................................................................................... .30LIST OF REFERENCES ...............................................................................................................31

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6 BIOGRAPHICAL SKETCH .........................................................................................................33

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7 LIST OF TABLES Table page 3-1 Age distribution .......................................................................................................... .......213-2 Ethnic distribution ....................................................................................................... .......21

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8 LIST OF FIGURES Figure page 3-1 Global pain ratings.. ..................................................................................................... ......223-2 TMD groups global (TMD) pain rating at in itial time point (prior to any QST) and seven days post-treatment. .............................................................................................. 233-3 Effects of capsaicin on thermal pain threshold within subject comparison.. ..................... 243-3 Effects of capsaicin on thermal pain threshold within subject comparison. ...................... 253-4 Pressure pain threshold changes.. ...................................................................................... 26

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9 Abstract of Dissertation Pres ented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy EFFECTS OF HIGH DOSE CAPSAICIN ON FACIAL PAIN PERCEPTION By Benjamin K. Campbell May 2009 Chair: John K. Neubert Major: Dental Sciences A significant number of individuals su ffer chronic pain associated with temporomandibular joint disorders (TMD); however there still remain questions regarding the underlying pain mechanisms associated with TMD and therefore treatment strategies can be unclear. The transient receptor potential channel, vanilloid subfamily member 1 (TRPV1) has been identified as a target for pain control as it is expressed primarily on pain neurons and is involved with mediating inflammatory pain. Capsaicin, aTRPV1 agonist both activates and inactivates TRPV1-expressing neurons without producing tissue damage. A double-blinded, placebo-controlled clinical trial was used to inve stigate two specific aims: (1) To evaluate if chronic TMD patients modulate pain differently than normal control subjects; (2) To evaluate the analgesic efficacy of capsaicin in chronic TMD pa tients. Our results indicate that capsaicin significantly increases experimental pain in both TMD and non-TMD groups as compared to vehicle in the short term but s hows a decrease of TMD pain in the week following It has no effect on pressure pain threshold but it does decrease thermal pain threshold two hours after application though not one week out.

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10 CHAPTER 1 INTRODUCTION Background Orofacial pain disorders are estimated to affect 20% of the U.S. population [1] and are made up largely of temporomandibular joint disord ers (TMD). Estimates of the prevalence of painful TMD range from 3.6% to7% [2; 3] with wo men being affected more frequently than men by almost a two to one margin [1; 4]. A brief review of capsaicins role in pain research will provide some understanding as to why capsaicin may lead to an effective TMD pain treatment. Capsaicin and the Vanilloid Receptor TRPV1 Capsaicin is a lipophilic vani lloid compound [5] that m ay le ad to a novel analgesic drug that does not use the cyclooxygenase pathway or opi oid receptors [6]. Research has allowed the capsaicin receptor to be isolat ed, identified, and, in 1997, cloned [7]. The capsaicin receptor belongs to a nonselective, cation (sodium/calci um), ligand gated ion channel family named transient receptor potential channe l, vanilloid subfamily member 1 (TRPV1). It is involved in nociception, inflammation and in sensory signali ng [8-10]. The receptor responds to protons, temperatures greater than 43 C, and a number of vanilloid agen ts including capsaicin [11-13]. Additionally, TRPV1 is pr imarily expressed by A and C-fibers of afferent neurons which are, in part, responsible for the erythema, burning sensation, and sensitivity to other stimuli after application of capsaicin. In addition to studying the molecular biology, capsaicin has been clinically used and tested. A study involving subjects applying cap saicin 0.075% four times daily for three weeks demonstrated a degeneration of epidermal nerve fibers (ENF) by approximately 80% mostly at the epidermis [14]. Noting this effect, Malmberg et al. compared the e ffectiveness of low dose

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11 capsaicin (0.04% w/w) to a high dose (8% w/w) topically applied for set intervals up to 120 minutes. They found that the low dose had no e ffect on reduction of ENF nor reduction on heat sensitivity when compared to placebo. Yet, after a single dose of 8% capsaicin there was a reduction of ENF and desensitization to heat stimuli that were s een a week out [15]. The expectation of TRPV1 is that it could be a target for pain control [8], and if realized, a novel therapeutic approach inhibiting certain noc iceptive neurons while maintaining other motor and sensory functions [10]. Capsaicin Utility Studies indicate that capsaicin m ay have some analgesic value when applied topically at low doses (0.025% to0.075%). It has shown so me efficacy for treatment of chronic pain disorders such as rheumatoid arthritis (RA) and osteoarthritis (OA) [16; 17]. Two studies have shown favorable results for pa tients suffering post herpetic neuralgia (PHN) [18; 19], and capsaicin is the only drug labeled by the FDA for PHN. Questioning th e presumed efficacy of low dose capsaicin is a meta-analysis of previously published trials, which concluded that it had moderate to poor efficacy when treating chroni c neuropathic or muscul oskeletal pain [20]. Only one study has investigated the potential benefit of capsaicin, albeit low dose, as a treatment for TMD. This randomized, doubleblind, placebo controlled trial showed no difference in reduction of symptoms between th e 0.025% capsaicin and placebo groups suffering from TMD [21]. Significance The findings from previous OA and RA studi es engender some hope in treating TMD, which also has a joint pain component, with capsa icin by targeting TRPV1, as it plays a role in

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12 inflammation and pain. The literature, though, has many studies questioning capsaicins analgesic effectiveness at low doses and there are no well controlled an algesic studies of 8% capsaicin. With only one study evaluating capsa icins resolution of TMD pain, albeit low dosing, there is a definite need to explore the effects of higher dose topical capsaicin in wellcontrolled, randomized trials before conclusions can be drawn about targeting TRPV1 as an effective method for controlling TMD pain and ultimately chronic pain. Hypothesis and Specific Aims We proposed a double-b lind, placebo-controlled c linical trial to inve stigate two specific aims: (1) To evaluate if chronic TMD patient s modulate pain differently than normal control subjects; (2) To evaluate the analgesic efficacy of capsaicin in chronic TMD patients. We hypothesized that patients suffering from TMD w ill rate pain higher than control subjects following capsaicin application a nd TMD patients that receive capsa icin treatment will have a significant reduction in their pain compared to those receiving vehicle treatment.

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13 CHAPTER 2 METHODS Subject Recruitment and Randomization Study proto cols followed the guidelines of the Institutional Review Board of the University of Florida. The targeted study gr oup was those that suffer from TMD and healthy, control subjects (referred to as non-TMD subjects) that we re identified through advertising within the greater Gainesville, FL region. Treatments were randoml y assigned via a random number generator and syringes were labeled wi th a study protocol num ber (protocol number designated active versus vehicle but still unknown to investigator or participant). All participants received compensation for their time. Inclusion Criteria Nor mal, healthy, female volunteers, age 18-65 years of age, American Society of Anesthesiologists (ASA) status 1 or 2, and deemed in good general health were recruited. This represents the age range of many chronic pain pa tients, including patients with TMD, and the exclusive gender was selected since there are a higher proportion of females (>2:1 female: male) that develop TMD. In addition to the same age and gender requ irements, the TMD patients inclusion criteria also required subjects to have TMJ pain of greater than six mont hs duration, who rated their pain a three or greater for the week that immediately preceded the initia l testing date, and meeting the Research Diagnostic Criteria (RDC), Group IIIa. Arthralgia of the temporomandibular joint (TMJ) [22]. The last criteria is met if they have no crepitus, a nd must have verified joint pain with palpation at either the lateral pole or at the posterior attachment and meet one of the

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14 following: Be able to point to either muscle or joint pain, joint or muscle pain on assisted/unassisted opening, or joint or muscle pain in right or left excursive movements. Exclusion Criteria Exclusion criteria are as follows: an ASA stat us 3-5, pregnant or breast-feeding m others, allergy to investigational drugs or to red chili peppers, pr esence of chronic disease (e.g. cardiovascular disease, liver dise ase, kidney disease, diabetes, et c.). Subjects with course crepitus of the TMJ or any subjects who had ta ken any pain medications, either over the counter or prescription, within 48 hours prio r to participating in the trial fo r either testing day were also excluded. Excluded medications included but were not limited to aspirin, ibuprofen, acetaminophen, hydrocodone, or steroids. No exclus ions were made based on race, gender, or religion. General Once the subject had the study explained and sign ed the Inform ed Consent form, they were then asked to complete a health history quest ionnaire and the Resear ch Diagnostic Criteria (RDC) for Temporomandibular Disorders Histor y Questionnaire. The subjects were also informed that they could stop pa rticipating in the study or have the cream removed at any point. If they asked for removal of the cream earlier than the designated time, then the current time was noted, and they were then given the option to co ntinue with the rest of the study or stop all together. Blood pressure, temperature, results of pregnancy test, and visual analogue scale (VAS) and verbal ratings of that days TMD pain were recorded initially prior to any testing. Quantitative Sensory Testing Quantita tive sensory testing (QST) which includes heat and pressure pain threshold were completed for both normal and TMD subjects prio r to drug application (baseline), two hours

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15 post-drug application, and at the second visit one week later. All QST was practiced on the nondominant arm to acclimate the subj ect to the testing procedures. Pressure Pain A clinical grade pressure algometer (FPX 50--25 x 0.2N Wagner, Greenwich, Ct), which has a rubber tip, measured pressure pain threshol d by placing the probe tip perpendicular to the skin testing site and applying pre ssure in an increasing manner at a rate of 1Kg/sec. The subject signified the time of first painful response, at wh ich point the pressure ap plication ceased and the value recorded. The TMJ (site 1) and masseter (site 2) on both the right a nd left sides of the face were evaluated. After testing both sites bilaterally, VAS ratings of global pain were immediately recorded. Global pain was defined as clinical (TMD ) pain plus experimental pain. This test was repeated three times unless two of the three tests were not with in 0.5 Kg necessitating a fourth trial. Thermal Testing Changes in therm al sensitivity were assessed using Medoc Thermal Testing Device (Medoc Advanced Medical Systems, Durham, N. C.). Pain threshold was assessed using an ascending method of limits with a rate of rise equaling 0.5 C/sec., starting at 32 C. and not to exceed 53C. The thermode as applied on the skin overlying the masseter area and TMJ. Subjects indicated by pressing a button when they first felt pain immediately stopping the stimulus and the value was recorded. After applyi ng the heat to the first side of the face, a two and a half minute timer was starte d and then the heat probe was applied to the opposite side of face as before. At the sound of the timer a pain VAS reading was taken. A fourth trial was required if two of the thr ee trials recorded temperat ures were not within 1 C.

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16 Drug Application Form osa Laboratories supplied the capsaicin (T aoyuan, Taiwan), with the final 8% topical cream used was compounded by Westlab Pharmacy (Gainesville, FL). The control (vehicle) cream was the same topical solu tion but contained no capsaicin. The investigator applied 0.1ml cream to a 3 cm area overlying the affected TMJ and superficial masseter to be left on for two hours. The drug was applied to the right or left side randomly for subjects without TMD, whereas, fo r the TMD sufferers, the side that was more painful was studied. During the application the pa tient rated what their expected pain levels would be with the given treatment and also their desire for pain relief. Capsaicin-evoked pain intensity VAS ratings were collected every five mi nutes for the first half hour of the experiment; then every thirty minutes for the duration of th e two hours. At the end of the two hours, the subjects face was wiped clean with soaked ga uze of half and half cream followed by alcohol swabs to remove residual capsaicin. After removal of the cream the battery of te sts was repeated and patient dismissed. All subjects were phoned twenty four hours following the cream application to assess pain and adverse event experience. Furthermore, TMD patie nts rated their clinical pain for seven days using a VAS home diary and retu rned it on their second visit. The one week follow up consisted of performing the same QST followed by the RDC for Temporomandibular Disorders Physical Assessment (Axis I). The physical exam was completed by the Principal Investigator and included standard evaluation of the TMJ and mastic atory muscles. Pain ratings were recorded for each of these palpation sites.

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17 Measures Perceiv ed pain intensity, desire for pain relie f, and expected pain levels were measured using a slide algometer VAS [23] following capsaicin or vehicle cr eam application. In using the pain sensation intensity scale th e patient would slide the middle sl iding part of the device to the right for an indicator of greater pain sensation intensity. The a rrow at the extreme left meant no pain sensation at all and the arrow at the extrem e right indicated a pain sensation intensity that subject imagined to be the most intense that she could possibly experience. Similarly, sliding algometer VAS was used as the desire for relief s cale, with the arrow at the extreme left meaning no desire for pain relief and the arrow at the ex treme right representing the most intense desire for relief imaginable. Lastly, ra tings of expected pain level were anchored by the descriptors no expected pain on the left and the most intense pain imaginable on the right. These scales for expected pain levels, desire for pain relief and anxiety have been valida ted previously [23-25].

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18 CHAPTER 3 RESULTS Initia l Controls Results Demographics Initially 44 control (non-TMD) subjects were recruited with 21 receiving capsaicin and the rem aining 23 received vehicle. An additi onal 10 capsaicin non-TMD subjects were recruited to evaluate the effects of capsaicin on QST pe rformed one week later. Sixteen TMD subjects were recruited with eight receiv ing capsaicin and the remainder the vehicle. None of them dropped out but two participants (one from each of the TMD and non-TMD capsaicin groups) requested the cream to be removed prematur ely (before the two hour time limit) after drug application though they chose to pa rticipate in the remainder of the study. Their data was not included in the results. Table 3-1 summarizes the total number of subjects enrolled to date tabulated by age and table 3-2 by race excluding the two partic ipants who did not com plete all requirements. Experimental and Global Pain Application of capsaicin increa sed pain ratings as compared to vehicle-treatment in both healthy and TMD symptomatic subjects (Figure 3-1 ). W hen we evaluated the short-term effects of capsaicin versus vehicle treatments (up to 2 hours post-application) for the TMD and nonTMD groups, we found there was a significant increase in VAS ratings over time for the capsaicin treated group as compared to vehicle treated subjects (ANOVA, P<0.001). Individual subjects who were assigned to control and treatment group provided multiple repeated observations for subjective pain meas urements during 5, 10, 120 minutes and later, 1 to 7 days. Because the serial measurements and distinction between relatively short-term

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19 versus long-term effects were correlated according to the individual subjects, multilevel (hierarchical) linear model (=mixed model) was applied. This linear mixed model has some advantages: 1) does not require observations to be independent w ith constant variance; 2) can test the variability of individua l subjects random effect; 3) so me missing measures do not cause all data for an individual subj ect to be ignored. TMD groups gl obal (TMD) pain ra ting at initial time point (prior to any QST) and seven days post-treatment. The VAS measures during 5 to 120 min were significantly lower in the control vehicle group than in the capsaicin treatment group (P = 0.002). The VAS measures during 5 to 120 min were decreased over time (P < 0.001). The VAS measures during 1 to 7 days ( Figure 3-2. ) w ere significantly greater in the control vehicle group than in the capsaicin treatme nt group (P = 0.001). The VAS measures during 1 to 7 days showed an unknown tendency over time due to inadequate sample size (P < 0.001). The pattern of VAS measures was reversed in case of capsaicin treatment in the long run (P = 0.033). Thermal Pain Threshold Capsaicin and vehicle TMD groups have sim ilar baseline therma l pain thresholds and this comparison holds true for the Non-TMDs groups. Both TMD and non-TMD groups ( Figure 33A and B respectively) dem onstr ated a significant decrease in thermal pain threshold (-3.5 C and -5.4 C respectively) (Paired T test p < 0.05) at two hours post-capsa icin cream application. The thermal threshold recovered to baseline levels by one week, with no differences noted when compared to baseline values for either group. No significant thermal pain threshold differences were observed at any time of the post-vehicle te st sessions (+2 hr, 1 week) as compared to baseline levels ( Figure 3-3 A and B). Com parison of results for non-TMDs one week follow up

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20 (n=10) were compared to their own baseline average rather than the combined data of all capsaicin non-TMD subjects (n=30). Pressure Pain Threshold Both TMD and non-TMD subjects showed sim ila r pressure pain thre sholds respectively across time at baseline at both th e masseter and the TMJ. No si gnificant changes in pressure pain threshold across time emerged for non-TMD or TMD subjects ( Figure 3-1 A and B, respec tively) regardless if they received vehicle or capsaicin treatm ent as compared to baseline. Capsaicin TMD subjects (n=8) ha d a significantly lower thres hold of 2.01.08g (mean s.e.m., p<0.05) as compared to non-TMD controls (n=10) at 2.59.73g at QST baseline.

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21 Table 3-1. Age distribution Subject Treatment Normal TMD N MeanSD N Mean SD Control vehicle 23 22.56.9 8 25.8 12.2 Capsaicin 8% 30 28.010.6 7 29.3 12.3 Total 53 25.69.5 15 27.4 11.9 Two-way (2-factorial) ANOVA revealed that th ere is no significant difference in the age distribution neither between normal versus TM D subjects (P = 0.437), nor between control versus treatment groups (P = 0.127). Table 3-2. Ethnic distribution Ethnicity Normal subjects TMD patients Control Capsaicin 8% Total Control Capsaicin 8% Total Caucasian 12 (52.2) 20 (66.6) 32 (60.5) 5 (62.5) 5 (71.4) 10 (66.6) AfricanAmerican 2 (8.7) 2 (6.7) 4 (7.5) 1 (14.3) 1 (6.7) Hispanic 8 (34.8) 5 (16.7) 13 (24.5) 3 (37.5) 1 (14.3) 4 (26.7) Asian 1 (4.3) 3 (10.0) 4 (7.5) Fishers Exact statistic showed that there is no significant difference in th e ethnicity distribution neither between normal versus TMD subjects (P = 0.459), nor between cont rol versus treatment groups (P = 0.569). Percentage s are in the parentheses.

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22 A B Figure 3-1. Global pain ratings A)TMD and B)Non-TMDs global pain ratings (experimental and clinical pain if any) for up to tw o hours after capsaicin or vehicle cream application. Application of capsaicin increased reported pain as compared to vehicle in both healthy and TMD symp tomatic subjects. There wa s a significant increase in VAS ratings over time for the capsaicin treat ed group as compared to vehicle treated subjects (ANOVA, P<0.001).

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23 Figure 3-2. TMD groups global (TMD) pain rating at initial time point (pri or to any QST) and seven days post-treatment. The VAS measures during 5 to 120 min were significantly lower in the c ontrol vehicle group than in the capsaicin treatment group (P = 0.002). The VAS measures during 5 to 120 min were decreased over time (P < 0.001). The VAS measures during 1 to 7 da ys were significan tly greater in the control vehicle group than in the capsaicin treatment group (P = 0.001). The VAS measures during 1 to 7 days showed an unknown tendency over time due to inadequate sample size (P < 0.001). The pa ttern of VAS measures was reversed in case of capsaicin treatment in the long run (P = 0.033).

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24 A B Figure 3-3. Effects of capsaicin on thermal pain threshold within subject comparison. A) TMD (n=8)and B) non-TMD (n=30) capsaicin groups demonstrated a significant decrease in thermal pain threshold(-3.5 C and -5.4 C respectively) (Paired T test p < 0.05) at two hours post cream application. No cha nge was observed one week later A) TMD and C) non-TMD (n=10). No change of thermal pain threshold was observed at any time in the vehicle.

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25 C Figure 3-3. Effects of capsaic in on thermal pain threshold within subject comparison.

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26 A B Figure 3-4. Pressure pain thre shold changes. A) Non-TMDs and B) TMDs Pressure pain threshold changes following capsaicin or ve hicle application. TMJ pressure pain threshold was not significantly changed following either capsaicin or vehicle treatment, as compared to baseline leve ls nor between respec tive groups within the non-TMD or TMD subjects.

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27 CHAPTER 4 DISCUSSION Less TMD pain was reported in the week following capsaicin as compared to the vehicle. Capsaicin decreased thermal pain threshold two hours af ter application but not one week later it did not affect pressure pain thre shold across time. All groups were similar in age and ethnicity. Each finding will be discussed below. Figure 3-2 suggests that capsaicin may have some clinical benefits of relieving TMD pain disagreeing with a previous capsaicin TMD study that found no difference between the TMD and healthy control groups [21]. This discrepancy could be attributed to their use of low dose capsaicin to our high dose and that they collected their reported pain weekly whereas our study collected it daily. Therefore thei r interval in reporting pain ma y be too far apart. The data showed a difference between the TMD capsaicin and vehicle groups as a whole over the entire seven days post cream application but due to li mited recruitment of subjects tendency over the week is unknown. It is not too surprising that during the two hours after capsaicin application that both TMD and healthy subjects found it to be a painful experience that lasted for some time. An hour after capsaicin application the TMD group pain returned to or was below initial pain levels. The TMD group receiving vehicle had no increase in pain but was level and dropped off towards the end. As noted 2 of 38 individuals felt like the pa in was too much and did not want to continue suggesting that some of the population may have poor compliance with the present treatment modality. The thermal threshold results showed that re gardless of disease state of the group (TMD vs. non-TMD), the threshold decreased only on the si de ipsilateral to the capsaicin and was only

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28 seen at the two hour time point ra ther than seven days out. At first glance this finding seemingly contradicts previous findings of desensitization one week later af ter a two hour application of 8% capsaicin or three weeks later after multiple daily low dose capsaicin applications at the same skin site [14; 15]. The difference in the findi ngs is thermal sensitization determines when a subject first feels warmth (sensitiza tion) rather than pain due to h eat (thermal pain threshold) and both studies were not testing facial skin which may react differently than the arm or inner thigh. The decreased TMD pain over the course of th e week is seemingly incongruent with the thermal pain threshold that did not maintain a decrease one week out compared to baseline. These findings may be explained by the placebo effect. Although the pa tients were told that they may or may not get capsaicin, the burning sens ation likely made treatment assignment readily apparent to the women. They then might expect some relief. Alternatively, it is known that capsaicin can deplete neuropeptid es like substance P which has no relationship to thermal pain and therefore may decrease associated sy mptoms to inflammation around the TMJ. Lastly, the pressure pain threshold, no ma tter what grouping or comparisons to other groupings demonstrates that capsaicin has no eff ect in changing the thre shold both at two hours or one week after application a nd regardless the site tested (i .e. the masseter or TMJ). These findings argue that the peripheral and central effects of topical capsa icin do not influence perception of mechanical pressure pain. This finding is in co ntrast to findings regarding mechanical allodynia induced by topically applied 0.075% capsai cin [26]. However, that mechanical stimulus involved application of a moving light touch using a paint brush, which differs substantially from the pressure pain stimulus used in the current protocol.

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29 Limitations of this study in clude the relatively low n va lue for the TMD groups and so all conclusions are tentative and require further evaluation in a larger st udy. The study could be improved by including a seven day diary assessing the daily level of pain prio r to the initial visit so as to have a better baseline rather than a single time point to compare a whole weeks worth of global pain. Any experience with TMD patients suggests that the perceived pain is highly variable. Therefore it could be argued that in recruiting patien ts for our study we biased the study by recruiting patients that do not necessarily experience the stated pain that they came in with on a normal basis. Alternatively, including patients that w ould be recruited in a similar manner that would not undergo any QST testing or capsaicin application, would be given a seven day diary could also he lp tease out any bias.

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30 CHAPTER 5 CONCLUSIONS Our experim ental approach uti lized established quantitative sensory testing techniques in order to evaluate the effects of 8% capsaicin cream compared to placebo control cream in TMD and non TMD subjects. Capsaicin had no effect on pressure (mecha nical) pain threshold in both TMD and healthy individuals. Those subjects receiving capsai cin became sensitized to heat regardless if part of the TMD group or not. A trend for lowering pain in TMD capsaicin group suggests a possible therapy but more subjects are needed to evaluate this relationship thoroughly.

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31 LIST OF REFERENCES 1. Lipton JA, Ship JA, Larach-Robinson D. Es tim ated prevalence and distribution of reported orofacial pain in the United States. J Am Dent Assoc 1993;124(10):115-21. 2. Schiffman EL, Fricton JR, Haley DP, Shapiro BL. The prevalence and treatment needs of subjects with temporomandibular disord ers. J Am Dent A ssoc 1990;120(3):295-303. 3. Gameiro GH, da Silva Andrade A, Nouer DF, Ferraz de Arruda Veiga MC. How may stressful experiences contribute to the de velopment of temporomandibular disorders? Clin Oral Investig 2006. 4. LeResche L. Epidemiology of temporomandibular disorders: implications for the investigation of etiologic factors. Crit Rev Oral Biol Med 1997;8(3):291-305. 5. Rumsfield JA, West DP. Topical capsaicin in dermatologic and peripheral pain disorders. DICP 1991;25(4):381-7. 6. Szolcsanyi J. Forty years in capsaicin research for sensory pharmacology and physiology. Neuropeptides 2004;38(6):377-84. 7. Caterina MJ, Schumacher MA, Tominaga M, Rosen TA, et al. The capsaicin receptor: a heat-activated ion channel in the pa in pathway. Nature 1997;389(6653):816-24. 8. Caterina MJ, Julius D. The vanilloid receptor: a molecular gateway to the pain pathway. Annu Rev Neurosci 2001;24:487-517. 9. Szallasi A, Appendino G. Vanilloid receptor TRPV1 antagonists as the next generation of painkillers. Are we putting the cart before the horse? J Med Chem 2004;47(11):2717-23. 10. Karai L, Brown DC, Mannes AJ, Connelly ST, et al. Deletion of vanilloid receptor 1expressing primary afferent ne urons for pain control. J C lin Invest 2004; 113(9):1344-52. 11. Gunthorpe MJ, Benham CD, Randall A, Davis JB The diversity in the vanilloid (TRPV) receptor family of ion channels. Trends Pharmacol Sci 2002;23(4):183-91. 12. Tominaga M, Caterina MJ. Thermosensati on and pain. J Neurobiol 2004;61(1):3-12. 13. Szallasi A, Cruz F, Geppetti P. TRPV1: a therapeutic target fo r novel analgesic drugs? Trends Mol Med 2006;12(11):545-54. 14. Nolano M, Simone DA, Wendelschafer-Crabb G, Johnson T, et al. Topical capsaicin in humans: parallel loss of epidermal nerve fibers and pain sensation. Pain 1999;81(12):135-45. 15. Malmberg AB, Mizisin AP, Calcutt NA, von Stei n T, et al. Reduced heat sensitivity and epidermal nerve fiber immunostaining follo wing single appli cations of a highconcentration capsaicin pa tch. Pain 2004;111(3):360-7.

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32 16. McCarthy GM, McCarty DJ. Effect of topical capsaicin in the therapy of painful osteoarthritis of the hands. J Rheumatol 1992;19(4):604-7. 17. Deal CL, Schnitzer TJ, Lipstein E, Seibold JR et al. Treatment of arthritis with topical capsaicin: a double-blind trial. Clin Ther 1991;13(3):383-95. 18. Watson CP, Tyler KL, Bickers DR, Millikan LE et al. A randomized vehicle-controlled trial of topical capsaicin in the treatmen t of postherpetic neuralgia. Clin Ther 1993;15(3):510-26. 19. Peikert A, Hentrich M, Ochs G. Topical 0.025% capsaicin in chronic post-herpetic neuralgia: efficacy, predictors of response and long-term course. J Neurol 1991;238(8):452-6. 20. Mason L, Moore RA, Derry S, Edwards JE, et al. Systematic review of topical capsaicin for the treatment of chroni c pain. BMJ 2004;328(7446):991. 21. Winocur E, Gavish A, Halachmi M, Eli I, et al. Topical applicati on of capsaicin for the treatment of localized pain in the tem poromandibular joint area. J Orofac Pain 2000;14(1):31-6. 22. Dworkin SF, LeResche L. Res earch diagnostic criteria for temporomandibular disorders: review, criteria, examinations and specifi cations, critique. J Craniomandib Disord 1992;6(4):301-55. 23. Price DD, McGrath PA, Rafii A, Buckingham B. The validation of visual analogue scales as ratio scale measures for chronic and experimental pain. Pain 1983;17(1):45-56. 24. Price DD, Milling LS, Kirsch I, Duff A, et al. An analysis of factors that contribute to the magnitude of placebo analgesia in an expe rimental paradigm. Pain 1999;83(2):147-56. 25. Vase L, Robinson ME, Verne GN, Price DD. Th e contributions of suggestion, desire, and expectation to placebo eff ects in irritable bowel syndrome patients. An empirical investigation. Pain 2003;105(1-2):17-25. 26. Petersen KL, Fields HL, Brennum J, Sandr oni P, et al. Capsaicin evoked pain and allodynia in post-herpetic neur algia. Pain 2000;88(2):125-33. 27.

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33 BIOGRAPHICAL SKETCH Benjam in K. Campbell was born of goodly pare nts residing in Willard, Utah. He was active in his youth church program and scou ting, earning the Eagle Scout Award. After graduating Box Elder High School, he served a Spanish-speaking proselyting mission for the Church of Jesus Christ of Latter Day Saints for two years at his own expense in the foreign land of Idaho. In the summer of 1997, after the comp letion of his mission, he studied at Weber State University majoring in chemistry, minoring in Sp anish, and was awarded a Bachelor of Science degree in 2000. He took a year off from school, entering the workforce as a chemist and had a wonderful time working for Thatcher Chemical and Albion Laboratory. In March of 2003 he married a lovely and beautiful lady, Dana, and th ey had their first child, Grace, in May of 2004. After completing dental school, he was awarded his Doctor of De ntal Surgery degree in 2005. Upon completion of a one-year fellowship in orthodontics at the University of Florida, he entered their orthodontic program graduating in May 2009. He and his wife had two more children during his residency, Sadi e (July 2006) and Hayden (April 2008 ), and, yes, they plan to have more! He tries to live up to a quoted principle, No success outside of the home will compensate for failure in the home, when balancing lifes prioritiesf amily, work, and play