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Effects of Analgesics on Pre- and Post-Separator Pain

Permanent Link: http://ufdc.ufl.edu/UFE0022167/00001

Material Information

Title: Effects of Analgesics on Pre- and Post-Separator Pain
Physical Description: 1 online resource (33 p.)
Language: english
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: analgesics, drugs, ibuprofen, nsaids, orthodontics, pain, placement, post, pre, separators
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: Pain with orthodontic appliances plays a role in treatment acceptance and compliance. The literature, however, is inconclusive as to the preferred analgesic drug for management of orthodontic pain. Although most conclude that ibuprofen is an effective analgesic for mild to moderate pain associated with orthodontics, there is evidence in support of naproxen sodium and acetaminophen. The purpose of this study was to assess the effectiveness of three different analgesics (ibuprofen, naproxen sodium, and acetaminophen) administered prior to and after placement of separators, in reducing the incidence and severity of post-separator placement pain. The study also assessed the effectiveness of placebo administration, as well as the contribution of psychological factors and gender to the pain experience. Twenty-four non-orthodontic patients, 13 male and 11 female, participated in the study. Each subject randomly received one of four treatments: ibuprofen, naproxen sodium, acetaminophen or placebo. The dosing times were 1 hour prior to separator placement and 3 and 7 hours after separator placement. Prior to separator placement, subjects completed a State and Trait Anxiety Inventory, Positive Affect Negative Affect Schedule, a Masticatory Efficiency Test, and a Visual Analog Scale for expected pain and pain experienced with the Masticatory Efficiency Test. A pain dairy was kept for 24 hours. Subjects returned to the clinic after one week for separator removal. This protocol was followed twice more, at monthly intervals. By the end of the three months, each subject received three of the four treatments. The order of treatment drugs administered was randomized. Based on mixed model analyses (p < 0.05), pain following separators was significantly related to the treatment drug and the time following separator placement. Administering ibuprofen pre- and post- separator placement significantly reduced pain compared with placebo. The analgesic effects diminished by day 2, resulting in peak pain levels and decreased chewing efficiency at this time. The expected pain also played a role in experienced pain; subjects who expected more pain also reported more pain.
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.
Thesis: Thesis (M.S.)--University of Florida, 2008.
Local: Adviser: Wheeler, Timothy T.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2010-05-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022167:00001

Permanent Link: http://ufdc.ufl.edu/UFE0022167/00001

Material Information

Title: Effects of Analgesics on Pre- and Post-Separator Pain
Physical Description: 1 online resource (33 p.)
Language: english
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2008

Subjects

Subjects / Keywords: analgesics, drugs, ibuprofen, nsaids, orthodontics, pain, placement, post, pre, separators
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: Pain with orthodontic appliances plays a role in treatment acceptance and compliance. The literature, however, is inconclusive as to the preferred analgesic drug for management of orthodontic pain. Although most conclude that ibuprofen is an effective analgesic for mild to moderate pain associated with orthodontics, there is evidence in support of naproxen sodium and acetaminophen. The purpose of this study was to assess the effectiveness of three different analgesics (ibuprofen, naproxen sodium, and acetaminophen) administered prior to and after placement of separators, in reducing the incidence and severity of post-separator placement pain. The study also assessed the effectiveness of placebo administration, as well as the contribution of psychological factors and gender to the pain experience. Twenty-four non-orthodontic patients, 13 male and 11 female, participated in the study. Each subject randomly received one of four treatments: ibuprofen, naproxen sodium, acetaminophen or placebo. The dosing times were 1 hour prior to separator placement and 3 and 7 hours after separator placement. Prior to separator placement, subjects completed a State and Trait Anxiety Inventory, Positive Affect Negative Affect Schedule, a Masticatory Efficiency Test, and a Visual Analog Scale for expected pain and pain experienced with the Masticatory Efficiency Test. A pain dairy was kept for 24 hours. Subjects returned to the clinic after one week for separator removal. This protocol was followed twice more, at monthly intervals. By the end of the three months, each subject received three of the four treatments. The order of treatment drugs administered was randomized. Based on mixed model analyses (p < 0.05), pain following separators was significantly related to the treatment drug and the time following separator placement. Administering ibuprofen pre- and post- separator placement significantly reduced pain compared with placebo. The analgesic effects diminished by day 2, resulting in peak pain levels and decreased chewing efficiency at this time. The expected pain also played a role in experienced pain; subjects who expected more pain also reported more pain.
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.
Thesis: Thesis (M.S.)--University of Florida, 2008.
Local: Adviser: Wheeler, Timothy T.
Electronic Access: RESTRICTED TO UF STUDENTS, STAFF, FACULTY, AND ON-CAMPUS USE UNTIL 2010-05-31

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2008
System ID: UFE0022167:00001


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1 EFFECTS OF ANALGESICS ON PREAND POST-SEPARATOR PAIN By SHREENA PATEL 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 2008

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2 2008 Shreena Patel

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3 ACKNOWLEDGMENTS I would like to thank m y chair and member s of my supervisory committee for their mentoring and guidance with the study. I am gratef ul to my family and friends for their support and encouragement through the years.

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4 TABLE OF CONTENTS page ACKNOWLEDGMENTS...............................................................................................................3 LIST OF TABLES................................................................................................................. ..........5 LIST OF FIGURES.........................................................................................................................6 ABSTRACT.....................................................................................................................................7 CHAP TER 1 INTRODUCTION....................................................................................................................9 2 METHODS.............................................................................................................................12 Subjects and Inclusion Criteria............................................................................................... 12 Methods..................................................................................................................................12 Data Analysis..........................................................................................................................14 3 RESULTS...............................................................................................................................16 4 DISCUSSION.........................................................................................................................22 5 CONCLUSIONS.................................................................................................................... 29 LIST OF REFERENCES...............................................................................................................30 BIOGRAPHICAL SKETCH.........................................................................................................33

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5 LIST OF TABLES Table Page 3-1 Descriptive statistics..................................................................................................... .....18 3-2 Mixed model analysis* with estimates of fixed effects (treatm ent and timepoint)........... 20 3-3 Mixed model analysis* with estimate s of fixed effects and expected pain ....................... 21

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6 LIST OF FIGURES Figure Page 2-1 Treatment timeline for all subjects to be repeated three tim es at monthly intervals......... 15 3-1 Mean pain scores for treatment drugs at each timepoint................................................... 18 3-2 Mean masticatory efficiency for treatment drugs at baseline and 24 hrs post-separator placem ent...................................................................................................................... .....18 3-3 Mean masticatory efficiency at baseline and 24 hrs for each period. ................................ 19 3-4 Mean masticatory efficiency at baseline and 24 hrs for non-responders and responders. .........................................................................................................................19 3-5 Mean expected and placement pain for non-responders and responders. .......................... 20

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7 Abstract of Thesis Presen ted to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science EFFECTS OF ANALGESICS ON PREAND POST-SEPARATOR PAIN By Shreena Patel May 2008 Chair: Timothy T. Wheeler Major: Dental Sciences Pain with orthodontic appliances plays a ro le in treatment acceptance and compliance. The literature, however, is inconc lusive as to the preferred an algesic drug for management of orthodontic pain. Although most conclude that ibuprofen is an e ffective analgesic for mild to moderate pain associated with orthodontics, there is evidence in support of naproxen sodium and acetaminophen. The purpose of this st udy was to assess the effectiveness of three different analgesics (ibuprofen, naproxen sodium, and acet aminophen) administered prior to and after placement of separators, in reducing the incidence and severity of post-separator placement pain. The study also assessed the effectiveness of plac ebo administration, as well as the contribution of psychological factors and gender to the pain e xperience. Twenty-four non-orthodontic patients, 13 male and 11 female, participated in the study. Each subject randomly received one of four treatments: ibuprofen, naproxen sodium, acetam inophen or placebo. The dosing times were 1 hour prior to separator placement and 3 and 7 hours after separator placemen t. Prior to separator placement, subjects completed a State and Trait Anxiety Inventory, Positive Affect Negative Affect Schedule, a Masticatory Efficiency Test, and a Visual Analog Scale for expected pain and pain experienced with the Masticatory Efficien cy Test. A pain dairy was kept for 24 hours. Subjects returned to the clinic after one week for separator rem oval. This protocol was followed

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8 twice more, at monthly intervals. By the end of the three months, each subj ect received three of the four treatments. The order of treatment drugs administered was randomized. Based on mixed model analyses (p<0.05), pain following separato rs was significantly re lated to the treatment drug and the time following separator placement. Administering ibuprofen preand postseparator placement significantly reduced pain compared with placebo. The analgesic effects diminished by day 2, resulting in peak pain levels and decreased chewing efficiency at this time. The expected pain also played a role in experienced pain; subjects who ex pected more pain also reported more pain.

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9 CHAPTER 1 INTRODUCTION Pain is a widespread concern in the field of dentistry with no exception to orthodontics. Between 90 and 95% of patients undergoing orthodon tic treatm ent report pa in with appliances.1-3 Pain with appliances appears to play a role in treatment acceptance and compliance.4-7 A survey of patients attitudes toward or thodontic treatment indicated that pain is the most discouraging aspect of treatment and the primary reason for wanting to discontinue care.8 Discomfort may be felt with placement of separators and initial wires, as well as during adjust ment of appliances at subsequent appointments. With such a high incidence of discomfort, pain control and management is an obvious interest for clinicians and pa tients alike. Pain following orthodontic treatment is usuall y felt within a few hours, reaching maximum levels 24 hours later. After one week, th e level of discomfort usually decreases.9 There is evidence that about 25% of patients still experience pain after 7 days of appliances.3,10 Differences in treatment; whether separators, appliances, or archwires; may explain the conflicting results among these studies. A rando mized clinical trial conducted by Jones and Chan11 reported similar findings with the highest pain scores noted the morning following the placement of initial archwires. Continued discomfort was recorded for 5 to 6 days. Managing orthodontic pain with analgesics has been studied more recently. 9 In particular, non-steroidal anti-inflammatory drugs (NSAIDs) are often used due to their analgesic, antiinflammatory, and anti-pyretic effects. Comm only used NSAIDs include ibuprofen (such as Advil or Motrin) and naproxen (such as Aleve). The mechanism of action of these drugs is due to the inhibition of cyclooxygenase (COX). Inhibiting COX prevents the synthesis of prostaglandins and thromboxanes from arachid onic acid. NSAIDs act in the periphery by interfering with pain signals that result from tissue injury. They minimize the activation and

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10 sensitization of peripheral nociceptors, which in turn minimizes noxious input into the central nervous system.12 Thus, post-treatment pain has reduced se verity and duration. If these drugs are not taken, peripheral sensitization occurs, eventually leading to prolonged activation of pain pathways, and evoking changes at the spinal cord level. This central sensitization increases activity of dorsal horn neurons and leads to amplified and intense pain.13-15 Due to the gastrointestinal side effects a ssociated with NSAIDs, acetaminophen, the most common brand name of which is Tylenol, may be recommended.14 Acetaminophen is classified as a non-opiod analgesic with anal gesic and anti-pyretic effects.12 It is commonly prescribed to treat fever, headaches, colds, and minor aches and pain. Acetaminophen does not have the antiinflammatory component that is characteristic of NSAIDs. Recently, it wa s reported that this drug selectively blocks a variant of the COX en zyme, which is different from COX-1 and COX2.16 This enzyme, which is only expressed in the brain and the spinal cord, is now referred to as COX-3. While the exact mechanism of acti on is unknown, it is thought that acetaminophen relieves pain by eleva ting the pain threshold. Considering the high prevalence of pain with orthodontic treatment, it is surprising that there is limited research in its management. Ngan et al.9 was the first to evaluate analgesics to control discomfort associated with orthodontic treatment. Th e authors administered 400 mg ibuprofen or 650 mg aspirin immediately follow ing separator or initia l archwire placement. Steen Law et al.17 took it a step further and instructed subjects to also take a dose of 400 mg ibuprofen 1 hour prior to separator placement. Both studies found pain reduction with ibuprofen, however, Steen Law et al. found significantly less pain on chewing at 2 hours post placement in subjects who received ibuprofen 1 hour prior to separators, even when compared to those who received ibuprofen only post-sepa rator placement. Minor et al.18 also supported administration of

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11 ibuprofen preand postseparator placement to d ecrease amount of pain experienced at 6 hours, bedtime, and morning afte r separator placement. Although the previous studies onl y evaluated NSAIDs in pain management, Polat et al.19 studied several different anal gesics. They found that naproxe n sodium and aspirin more effectively reduced pain compared with ibuprofe n, flurbiprofen, and plac ebo. Visual analog scale pain ratings following acetaminophen administra tion were only slightly higher than after naproxen sodium and aspirin. The subjects took doses one hour prior to initial bonding of appliances, and a final dose 4 hours after bonding. Interestingly, Polat et al. was the first group to study acetaminophen to reduce orthodontic pain. Most recen tly, Bird et al.20 found no significant differences in pain over a 24 hour pe riod following a single dose of acetaminophen or ibuprofen administered 1 hour prior to separator placement. Based on the literature, it is apparent th at there is no accepted regimen for treating orthodontic pain. Previous studies have been inconclusive as to the preferred analgesic drug to recommend to patients. Although most conclude that ibuprofen is an effec tive analgesic for mild to moderate pain associated with orthodontics, there is evidence in support of naproxen sodium and acetaminophen. It is important to realize that only a handful of studies have been conducted on this topic, and they are of limited value due to small sample size and individual variability. The objective of this prospective, randomize d, double blind, cross-over c linical trial is to compare the effectiveness of three different analgesic drugs (ibuprofen, naproxen sodium, or acetaminophen) administered to reduce the incide nce and severity of pain following placement of separators. The study will also evaluate the effectiveness of placebo administration prior to and after placement of separators as well as assess the contribu tion of psychological factors and gender to the pain experience.

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12 CHAPTER 2 METHODS Subjects and Inclusion Criteria A sa mple of twenty-four non-orthodontic subjec ts presented to the University of Florida Orthodontic Clinic for separator placement. Each participant met the follo wing inclusion criteria: 1) at least 13 years of age and no older than 30, 2) females must consent to a pregnancy test and could not be pregnant, 3) have second premolar s, first molars, and second molars that are in contact, therefore requiring the placement of two separators in each of four quadrants, 4) not taking any steroidal or non-ster oidal pain medications or any other anti-pain drugs, 5) no contraindications or adverse reactions to ibuprofen, naproxe n sodium, or acetaminophen, 6) no contraindications or adverse reactio ns to nuts, 7) written informed consent for participation in the study, 8) not need antibiotic prophylaxis prior to major dent al treatment. Methods Each subject was random ized to receive one of four treatments: ibuprofen, naproxen sodium, acetaminophen or placebo. The dosing time s for each treatment were one hour (D1) prior to separator placement, and three (D2) and seven (D3) hours after separator placement. Separators were removed after one week. One month later, subjects returned to the clinic, and received a different treatment drug with the sa me dosing protocol. After waiting another month, they followed this schedule for a third time, a nd received a third treatment (Figure 2-1). At each monthly appointment, health and drug history we re reviewed and updated to ensure eligibility. By the end of the three months (periods), each su bject had received three of the four treatments. The order of treatment drugs administered was randomized. The dosing for each drug was the following: 400 mg ibuprofen at D1, D2 and D3; 500 mg naproxen sodium at D1, placebo at D2 a nd 250 mg naproxen sodium at D3; 650 mg

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13 acetaminophen at D1, D2, and D3; placebo at D1, D2, and D3. The Investigational Drug Service at Shands Hospital re-encapsula ted 200 mg tablets of ibuprof en, 250 mg tablets of naproxen sodium, and 325 mg tablets of acetaminophen; place bo tablets were made to match. Two tablets were taken at each dosing time. The Shands Phar macy dispensed the tablets; consequently the researcher was blinded to the treatment group when administering tests. Prior to time of first dosing (T0), the following instruments were completed by all subjects: expectation of pain following separator pl acement using a 100 mm Visual Analogue Scale (VAS) with anchors of no pain (0 mm) and worst pain imaginable (100mm)21 pre-existing affective state using the St ate and Trait Anxiety Inventory (STAI)22 and the Positive Affect Negative Affect Schedule (PANAS)23 masticatory efficiency test,24 for which subjects chewed a single bagged almond five times on the right side of the mouth without swallowing. This was repeated on the left side of the mouth with another bagged alm ond. VAS pain ratings as a consequence of chewing the almond were recorded. pregnancy test, of which results must be negative, for all female subjects Two separators (Ormco P/N 640-0080, Glendora, CA) were placed in each quadrant, mesial and distal to the 1st molar. The method of placement was under the contact for all subjects. Pain upon separator placement was recorded on a VAS. Over the next 24 hours, subjects recorded discomfort when biting, chewing, fitting front teeth together and fitting back teeth together in a VAS pain diary, similar to that used in other studies.9,17,25,26 More specificall y, recordings were taken at 2 hours post-separator placement (T1) 6 hours post-separator placement (T2), bedtime (T3), upon awakening (T4), and 24 hours post-separator placement (T5). The remaining two doses were self-administe red by the subject at times D2 and D3. At T5, the subject completed the masticatory effici ency test with VAS. T1, T2, T5, D2, and D3 times were provided for the subject in the pain diary. The completed pain diary and the chewed

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14 bagged almonds were brought to the next appointment, one week later, at which time separators were removed. To analyze the chewed almonds, the whole sample was weighed, the sample was sieved through a #10 mesh, and the separated sample was weighed. The bite efficiency was determined as the percent of the original sample that passed through the sieve. Data Analysis Descriptive statistics were calculated for pain scores and masticatory chewing efficiency at each timepoint for the different treatment groups. Friedman non-parametric test was used to determine differences in mean pain scores be tween treatment groups. The relationship between chewing efficiency and treatment or period was also examined. Mixed models were used to examine pain ra tings over time. The primary model included the sum of pain ratings (biting, ri ght and left; chewing, ri ght and left; fitting back teeth together; and fitting front teeth together at each timepoint). The following variables were included in the model: treatment, period, prior treatment (assess carry-over effects), time point, and treatment by timepoint interaction. Th e interaction allowed the pain res ponse pattern to vary over time depending on treatment group. The impact of a dding additional covariat es (expected pain, psychological variables, and gender) to the primary model was also examined. For all analyses, a p-value of less than 0.05 was considered statistically significant. A power analysis was not carried out, as preliminary data re garding the correlation of pain measures over treatment type is lacking.

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15 Figure 2-1. Treatment timeline for all subjects to be repeated thr ee times at monthly intervals. To D1 Tx T1 D2 T2 D3 T3 T4 T5 400 mg Ibuprofen 400 mg Ibuprofen 400 mg Ibuprofen 500 mg Naproxen sodium Placebo 250 mg Naproxen sodium 650 mg Acetaminophen 650 mg Acetaminophen 650 mg Acetaminophen Consent Randomize Record height / weight Expected pain rating STAI, PANAS Masticatory efficiency test Experienced pain rating Placebo Experienced pain rating Pain Diary Placebo Pain Diary Placebo Pain Diary Pain Diary Masticatory efficiency test, Experienced pain rating, Pain Diary -1.25 hr -1 hr Separator Placement +2 hr +3 hr +6 hr +7 hr BedTime WakeUp 24 hr

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16 CHAPTER 3 RESULTS The descriptive statistics for the sample are li sted in Table 3-1. The sample consisted of 11 females (46%), and 13 males (54%). As shown in Figure 3-1, subjects who took ibuprofen reported significantly less pain than those who took placebo at 2 and 6 hours post-sepa rator placement, as well as at bedtime and awakening (p=.0035). Acetaminophen and na proxen sodium did not show significant differences compared with placebo at any of the timepoints. By 24 hours post-separator placement, which was 17 hours after the last medicat ion dose, pain levels returned to those of placebo for all subjects (p>0.05). Across treatment, differences in pain levels reported for each timepoint were statistically significant fr om each other (p<.0001), except for 6 hours and bedtime (p=.4085). For all treatment groups, chewing efficiency de creased from baseline to 24 hours (Figure 3-2). The difference was statisti cally significant (p=.0355). No signi ficant differences were seen among the 4 treatments at either baseline or 24 hours. There was a significant (p=.0226) improvement in baseline chewing efficiency at period 3 compared with periods 1 and 2 (Figure 3-3). Interestingly, 4 of the 24 subjects, termed non-responders, reported lower pain levels compared with the rest of the sample, the r esponders. Both expected pain and pain on placement were lower in non-responders compar ed with responders (Figure 3-4). Nonresponders also had higher chewing efficien cy 24 hours after separator placement than responders (Figure 3-5). These differe nces, however, were not significant. Mixed model analyses illustrate the impact of treatment and timepoint on reported pain. The intercept in Table 3-2 repr esents the pain score, 30.70 out of 100, which is altered depending

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17 on treatment drug and timepoint. For example, 7.89 w ould be subtracted from the pain score of a subject taking ibuprofen. In contrast, only 3.67 would be subt racted for acetaminophen. At 2 hours, 16.46 is subtracted from the pain score, wi th less taken away as the timepoint approaches 24 hours. Including expected pain in the mixed model s hows its correlation with pain score (Table 33). Similar to the previous example, the pain score is reduced by a sp ecific amount depending on which treatment drug the subject takes, again with the largest amount asso ciated with ibuprofen. The subjects expected pain is multiplied by 2.27 a nd added to the pain score. Accordingly, the more pain expected, the higher the pain score. E xpected pain and time are related; less pain is associated with earlier timepoints. Further analyses of the pain score assessed individual contributions of the components (chewing, biting, fitting front teeth together, and fitting back teet h together). Treatment drug was significant when fitting back teeth together (p=. 0046). However, significant differences did not emerge when fitting the front teeth together (p=.23). No significant differences were seen for the psychological assessment, STAI and PANAS, or gender.

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18 Table 3-1. Descriptive statistics N 24 Gender (% female) 45.8 Age (yrs) 26.4 (2.5) Weight (lbs) 167 (38.9) 0 5 10 15 20 25 30 35 40 2 hrs 6 hrs bedtimeawakening24 hrs Timepoint Pain Score Ibuprofen Acetaminophen Naproxen sodium Placebo * Figure 3-1. Mean pain scores for treatment drugs at each timepoint. 0 10 20 30 40 50 60 Baseline24 hrs TimepointMasticatory Efficienc y Ibuprofen Acetaminophen Naproxen sodium Placebo Figure 3-2. Mean masticatory efficiency for treatment drugs at baseline and 24 hrs postseparator placement.

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19 0 10 20 30 40 50 60 Baseline24 hrs TimepointMasticatory efficiency Period 1 Period 2 Period 3 Figure 3-3. Mean masticatory efficiency at baseline and 24 hrs for each period. 0 10 20 30 40 50 60 70 Baseline 24 hrs TimepointMasticatory Efficienc y Non-responders Responders Figure 3-4. Mean masticator y efficiency at baseline a nd 24 hrs for non-responders and responders.

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20 0 1 2 3 4 5 6 7 Non-responders Responders SubjectsPain Score Expected pain Placement pain Figure 3-5. Mean expected and placement pain for non-responders and responders. Table 3-2. Mixed model analysis* with estimate s of fixed effects (treatment and timepoint) Parameter Estimate Std Error Pr > t Intercept 30.70 2.70 <.0001 Ibuprofen -7.89 2.59 0.0035 Naproxen sodium -5.04 2.59 0.0563 Acetaminophen -3.67 2.59 0.1614 Placebo 0 2 hrs -16.46 1.42 <.0001 6 hrs -11.64 1.32 <.0001 Bedtime -10.90 1.16 <.0001 Awakening -5.74 0.89 <.0001 24 hrs 0 <.0001 *Dependent variable: pain score

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21 Table 3-3. Mixed model analysis* with esti mates of fixed effects and expected pain Parameter Estimate Std Error Pr > t Intercept 21.45 3.22 <.0001 Ibuprofen -6.54d 2.46 0.0103 Naproxen sodium -3.45 2.47 0.1679 Acetaminophen -1.75 2.49 0.4853 Placebo 0 2 hrs -9.43 2.27 <.0001 6 hrs -5.92 2.12 0.0056 Bedtime -7.25 1.88 0.0001 Awakening -6.64 1.45 <.0001 24 hrs 0 Expected pain 2.27 0.48 <.0001 Exp pain x 2 hrs -1.99 0.52 0.0001 Exp pain x 6 hrs -1.62 0.48 0.0009 Exp pain x bedtime -1.03 0.43 0.0157 Exp pain x awakening 0.26 0.33 0.4353 Exp pain x 24 hrs 0 *Dependent variable: pain score

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22 CHAPTER 4 DISCUSSION The present study was conducted as a prospective random ized double blind crossover clinical trial on 24 subjects to evaluate the e ffectiveness of analgesic drugs administered to reduce the incidence and severity of pain fo llowing placement of separators. Based on the results, pain following separators was significantly related to the treatment drug and the time following separator placement. In particular subjects who received ibuprofen reported significantly less pain than subjects who recei ved placebo. These results are consistent with previous studies17,18,26,27 in support of preand posttr eatment ibuprofen. Bird et al.,20 however, found no significant differences in post-separator pain with administration of acetaminophen or ibuprofen. Yet, the drugs were only administered 1 hour prior to separator placement, with no follow-up doses. Polat et al.19 studied several different analgesics, and recommended acetaminophen over naproxen sodium or aspirin. While subjects who took naproxen sodium and aspirin felt almost no pain at 24 hours, the ac etaminophen group showed similar pain scores, without the side effects associated with NSAIDs in regards to tooth movement and gastrointestinal. Compared with placebo, the results from this study f ound statistically significant differences only for ibuprofen, not naproxen so dium or acetaminophen. There are differences between this study and Polat et als.19 study in regard to drugs ad ministered, dosing, and time; age of subjects; and stimulus to induce pain. While 1100 mg naproxen sodium was administered in Polat et als. study, only 750 mg were used in the current study. The higher dose in the former study may help explain why naproxen sodium was effective in lowering orthodontic pain. Considering naproxen sodium approached signif icance compared with placebo (p<.0563), it is possible that administering a slig htly higher dose may have resulted in significance. The subjects

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23 in the present study were adults and separators were used to induce pain. In the contrary, subjects in Polat et als. study were adol escents, and initial ar chwires were placed to induce pain. These differences may account for the conflicting results seen in the two studies. An important point to consider is study design. All the previous studies on managing orthodontic pain with analgesics have been para llel arm in which each su bject receives only one treatment, largely since the s ubject underwent orthodon tic treatment. In the current study, nonorthodontic subjects were selected. With the incomplete block crossover design, all subjects received three of the four possible treatments. Mu ch of the between patient variability that is associated with the subjective nature of pain can be eliminated. Because of this reduction in variance, and since the same patient is repeated ly tested, crossover st udies may have greater statistical power than parallel arm studies. Pain scores at the different timepoints all si gnificantly differed from each other, with the exception of 6 hours with bedtime. These re sults are comparable with Law et al.17 and Berhardt et al.,26 who found no differences in pain scores at 6 hours. A recent study18 reported significantly less pain at 6 hours, along with bedtime and awaken ing; not at 2 or 24 hours. Although all of these studies administered 400 mg ibuprofen 1 hour prior to separator placement, they varied on post-separator placement doses. The pre-placement ibuprofen group in Law et als. study did not receive any drug following placement of separators; differences were only seen at 2 hours. Berhardt et al. administered ibuprofen 1 hour prior to separator placement, and 5 hours after; differences were seen at 2 hours and bedtime. Ibuprofen is rapidly absorbed with peak serum concentrations 1 hours following oral administration. Its elimination half-lif e, the time it takes to be reduced to half its init ial level, is 2 hours.28 Acetaminophen has a similar half-life of 2 hours, while that of naproxen sodium is

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24 about 12 hours. In this study, subjects took three dos es of drugs at 4 hour in tervals, the first of which was 1 hour prior to placement. Two factors may explain the results from this study: one, the time separators were placed, since that ul timately affected the dosing schedule; two, the weight of subjects. The time that separators were placed was not consistent across individuals, and neither was bedtime. Accordingly more or less time may have elap sed between the third dose and bedtime. If separators were placed late in the day, then the third dose (taken 7 hours after placement for all subjects) would have been close to bedt ime. Thus, it makes sense that there would not be a significant difference in pa in levels between 6 hours and bedtime. Based on the pharmacodynamics, the drug would still be av ailable in the body. Upon awakening, most, if not all, of the drug would have been eliminate d, and as a result, significant differences were noted at that timepoint when compared to the previous. The other consideration may be individual weight differences (mean 167.9 lbs) Although weight was re corded, all subjects received the same dose. It would be of intere st to examine whether su bjects who weighed less felt less pain. When the summary pain scores were broken dow n into components, it was apparent that the treatment drug administered resulted in significant differences when fitting the back teeth together. Ibuprofen, naproxen sodium, and acetam inophen were all significantly different from placebo. The opposite was true when the subject fit the front t eeth together; treatment was no longer significant. Since the separators were pl aced posteriorly, in between the molars, fitting those teeth together was more pa inful than fitting the front teet h together. The analgesic effects of the drugs were apparent in the former situatio n since a substantial amount of pain was elicited. In the latter, less pain was repor ted, which may have masked the an algesic effects. Accordingly, significant differences among drugs did not emerge.

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25 For the baseline and 24 hour bite efficiency, no significant differences were seen among treatment drugs. The difference between the tw o timepoints was smaller in the ibuprofen group compared with the other trea tment groups. However, the difference was not statistically significant, and merely a trend. Significant di fferences are not expected since the baseline chewing efficiency was prior to administration of drugs. Also, by 24 hours, the analgesic effects were mostly gone with the dosing regimen followed in the study, As far as order goes, the day 1 efficiency seems to be improving over time, as subjects gained more experience with this test. This proves the validity of the assay. A possible explanation for the significant diffe rence in masticatory chewing efficiency between baseline and 24 hours is the Central Pattern Generator (C PG). The CPG is a network of neurons found in the brainstem or spinal cord th at can generate a rhythmic motor pattern on its own.29 Normally, the CPG inhibits the antagonist mu scles, jaw openers, from firing when the jaw closers are active. However, pain stimulates the trigeminal sensory nucleus during closing, shortening the phase of jaw closure. To make this happen, the CPG facilitates the jaw opening interneurons during closure; the jaw openers are active during clos ure. When subjects performed the masticatory chewing efficiency at 24 hours, the pa in levels were at their highest. At this time, subjects had significantly lower chewing efficiency compared with baseline, since the reflexes by CPG stopped the jaw from fully closing. This mechanism is protective, similar to reflex responses pulling a hand away from a hot stove. The expected pain was a significant factor in predicting the pain experience. This is in agreement with other studies29,30 reporting a positive correlation between psychological factors and perceived pain. A longitudinal population-based study by Maggirias and Locker30 evaluated psychological factors and pain associated with dental treatment. Re sults were based on 1422

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26 adult subjects who completed questionnaires. Th e authors found a str ong relationship between perceived pain and psychological factors; pain was more often reported by those patients with previous traumatic experiences, t hose who expected treatment to be painful, as well as those who were anxious about treatment. Pre-existing affective state was assessed using two psychological surveys, STAI22 and PANAS.23 STAI measures state (situational) and trait (personality) anxiety, while PANAS measures mood along separate dimensions of positive and negative affect. Both of these instruments have been widely used in clinical and experimental research to evaluate psychological factors. The addition of state and trait anxiety, and positive and negative affect did not improve the model; these variables did not contribute to the pain experience. This is in agreement with Minor et als.18 findings. While it was thought that subjects with higher anxiety, higher negative affect, and lower positive affect would report more pain, no significance was found. No statistically significant ge nder differences were shown in the study for pain levels and masticatory efficiency among the treatment groups. It is possible that th e sample size was not large enough to detect differences, given prev ious effect sizes that are only moderate.31 It is interesting that 4 of 24 subjects were non-responders to pain. It may take more to initiate an inflammatory response in these indi viduals. Because the small sample size and large standard deviation, no inferences can be made base d on this data. It can be speculated that there is a proportion of the population that does not re spond to acute pain. This group may be less pain sensitive due to a higher pain tolerance. Future studies may c onsider taking gingival crevicular fluid, GCF, samples to evaluate the biologi c response. There appeared to be no gender predilection, with half female and half male.

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27 There are concerns with the use NSAIDs to alleviate orthodontic pain. Orthodontic tooth movement requires remodeling of the periodontium, re sulting in inflammation, which leads to bone resorption.32 Inflammatory mediators, such as prostaglandin E and interleukin-1 are released and interact with bone cells, promoting bone resorption.33 Because NSAIDs function by interfering with prostaglandin synthesis from arachidonic acid, it is reasonable to question whether administering these medications to relie ve orthodontic pain will interfere with tooth movement. According to Profitt, most pain medications do not reach high enough blood levels to inhibit tooth movement.34 Oral administration of aspirin in guinea pigs inhibited prostaglandin synthesis in the bronchioles, but did not adversely affect tooth movement.35 In contrast, several studies have shown that the inhibi tion of prostaglandins by NSAIDs does in fact prevent or delay orthodontic tooth movement.36-39 It is important to consider th e length of time these medications are taken and amount administered. Short-term administration of NSAIDs will only temporarily affect prostaglandin levels ; long-term use of these drugs should be avoided.9,38 Research shows that doses of 2400-3200 mg per day of ibuprofen are required to achieve anti-inflammatory effects over analgesic effects.14 The doses being administered in this study do not reach antiinflammatory levels. There are several limitations to the study. The activities to e licit pain at each timepoint were not standardized. Subjects were instructed to bite on right and left, chew on right and left, fit back teeth together, and fit front teeth together. It is reasonable to assume that subjects in pain may not have bitten or chewed as hard as anothe r subject. This protocol developed by Ngan et al.,9 has been used by previous studies17,18,19,26,27 evaluating pain levels. A more reliable test may be to have subjects use an almond to standardi ze the activity, rather th an being simulated or perceived. Non-compliance with the protocol ma y also be a concern. Subjects were asked to

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28 administer the 2nd and 3rd doses on their own, as well record in the pain diary at specific times. Although the average ag e of subjects in the study was 26.4.5 years, many individuals receiving orthodontics are younger. Accordingly, the results from this study may not apply to them. Also, a placebo within each group would ha ve provided a baseline for comparison. When designing the study, it was thought that randomizing participants to all 4 treatment drugs, and hence 4 visits for separators, would overburden them. Alternatively, to maintain 3 treatment drugs per subject, each could have received pl acebo and 2 of the 3 drugs. Previous pain experience may also be a factor. The VAS s cale is a 100 mm scale, and the worst pain imaginable will likely vary across subjects, depending on previous experiences. Future direction may include administering me dications at more timepoints, possibly at bedtime or awakening. The half-life of ibuprof en and acetaminophen is about 2 hours, and that of naproxen sodium is about 12 hours.28 Because pain levels peak 24 hours following separator or initial archwire placement, it would be prude nt to recommend a dose a few hours prior to this time. Performing masticatory efficiency over seve ral days, in conjunction with analgesics, may provide insight into the associa tion of pain and chewing effici ency. In the current study, the drugs were most likely eliminated from the body when the subjects performed the masticatory chewing efficiency test at 24 hour s following separator placement.

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29 CHAPTER 5 CONCLUSIONS Ibuprofen adm inistered 1 hour prior to separator placement, and 3 and 7 hours following placement, reduces post-separator placement pain compared with placebo. Acetaminophen and naproxen sodium did not show significant diffe rences compared with placebo. The analgesic effects diminish by day 2, resulting in peak pain levels and decreased chewing efficiency at this time. Additional drugs may be necessary to mainta in analgesia. The expected pain also plays a role in experienced pain; patients who expect more pain also report more pain. Psychological assessment and gender did not a ffect the pain experience.

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30 LIST OF REFERENCES 1. Lew KK. Attitud es and perceptions of adults towards orthodontic treatment in an Asian community. Community Dent Oral Epidemiol 1993; 21:31-35. 2. Kvam E, Gjerdert NR, Bondevik O. Trau matic ulcers and pain during orthodontic treatment. Community Dent Oral Epidemiol. 1987; 15:104-107. 3. Scheuer PA, Firestone AR, Burgin WB. Per ception of pain as a result of orthodontic treatment with fixed appliances. Eur J Orthod. 1996; 18:349-357. 4. Sergl HG, Klages U, Zentner A. Pain a nd discomfort during orthodontic treatment: causative factors and effects on compliance. Am J Orthod Dentofacial Orthop. 1998; 114:684-691. 5. Doll GM, Zentner A, Klages U, Sergl HG. Relationship between patient discomfort, appliance acceptance, and complia nce in orthodontic therapy. J Orofac Orthop. 2000; 61:398-413. 6. Egolf RJ, BeGole EA, Upshaw HS. Factors associated with orthodont ic patient compliance with intraoral elastic and headgear wear. Am J Orthod Dentofacial Orthop 1990; 97:336348. 7. Bartsch A, Witt E, Sahm G, Schneider. Correlates of objective patient compliance with removable appliance wear. Am J Orthod Dentofacial Orthop 1993; 104:378-386. 8. Oliver RG, Knapman YM. Attitude s to orthodontic treatment. Br J Orthod. 1985; 12:179188. 9. Ngan P, Wilson S, Shanfeld J, Amini H. The e ffect of ibuprofen on the level of discomfort in patients undergoing orthodontic treatment. Am J Orthod Dentofacial Orthop. 1994; 106:88-95. 10. Bergius M, Berggren U, Kiliaridis S. Experien ces of pain during an orthodontic procedure. Eur J Oral Sci 2002; 110:92-88. 11. Jones M, Chan C. The pain and discomfort experienced during orthodontic treatment: a randomized controlled clinical trial of two initial aligning archwires. Am J Orthod Dentofacial Orthop. 1992; 102:373-381. 12. Dionne RA, Cooper SA. Evaluation of preopera tive ibuprofen for postoperative pain after removal of third molars. Oral Surg Oral Med Oral Path Oral Radiol Endod. 1978; 45:851856. 13. Woolf CJ, Chong MS. Preemptive analgesia treating postoperative pain by preventing the establishment of central sensitization. Anesth Anal. 1993; 77:362-379.

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31 14. Mehlisch DR, Sollecito WA, Helfrick JF, Leibold DG, Markowitz R, Schow CE Jr, Schultz R, Wait DE. Multicenter clinical tr ial of ibuprofen and acetaminophen in the treatment of postope rative dental pain. JADA 1990; 121:257-263. 15. Urquhart E. Analgesic agen ts and strategies in the dental pain model. J Dent. 1994; 22:336-341. 16. Swierkosz TA, Jordan L, McBride M, McGough K, Devlin J, Botting RM. Actions of paracetamol on cyclooxygenases in tissue a nd cell homogenates of mouse and rabbit. Med Sci Monit. 2002; 8:BR496-503. 17. Steen Law SL, Southard KA, Law AS, L ogan HL, Jakobsen JR. An evaluation of preoperative ibuprofen for treatment of pa in associated with orthodontic separator placement. Am J Orthod Dentofacial Orthop. 2000; 118:629-635. 18. Minor V, Marris CK, McGorray S, Yezierski R, Fillingim R, Logan H, Wheeler TT. Effects of preoperative ibupr ofen, anxiety, and gender on post-separator placement pain; Master of Science Thesis, University of Florida 2006. 19. Polat O, Karaman A. Pain control du ring fixed orthodontic appliance therapy. Angle Orthod. 2005; 75:214-219. 20. Bird S, Williams K, Kula K. Preoperative acetaminophen vs ibuprofen for control of pain after orthodontic se parator placement. Am J Orthod Dentofacial Orthop. 2007; 132:504510. 21. Seymour RA, Simpson JM, Charlton JE, Phillip s ME. An evaluation of length and endphrase of visual analogue scales in dental pain. Pain. 1985; 21:177-185. 22. Spielberger CD. State-Trait Anxiety Inventory : a comprehensive bibliography Palo Alto, CA: Consulting Psychologists Press, Inc; 1989. 23. Watson D, Clark LA, Tellegen A. Developmen t and validation of brief measures of positive and negative aff ect: the PANAS scales. J Pers Soc Psychol. 1988; 54:1063-1070. 24. Al-Ali F, Heath MR, Wright PS. Simplified method of estimating masticatory performance. J Oral Rehabil. 1999; 26:678-683. 25. Ngan P, Kess B, Wilson S. Perception of discomfort by patients undergoing orthodontic treatment. Am J Orthod Dentofacial Orthop. 1989; 96:47-53. 26. Bernhardt MK, Southard KA, Batterson KD, Logan HL, Baker KA, Jakobsen JR. The effect of preemptive and/or postoperativ e ibuprofen therapy for orthodontic pain. Am J Orthod Dentofacial Orthop. 2001; 120:20-27. 27. Bradley R, Ellis P, Tho mas P, Bellis H, Ire land A, Sandy J. A randomized clinical trial comparing the efficacy of ibuprofen and para cetamol in the control of orthodontic pain. Am J Orthod Dentofacial Orthop. 2007; 132:511-517.

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32 28. PDR health [database on the Internet]. Th omson Physicians Desk Reference. C2007 [accessed 11/07] Available from: http://www.pdrhealth.com/home/home.aspx. 29. Firestone AR, Scheurer PA, Burgin WB. Patie nts anticipation of pa in and pain-related side effects and their perception of pain as a result of orthodontic treatment with fixed appliances. Eur J Orthod. 1999; 21:387-396. 30. Maggirias J, Locker D. Psychological factors and perceptions of pa in associated with dental treatment. Community Dent Oral Epidemiol. 2002; 30:151-159. 31. Riley JL, Robinson ME, Wise EA, Myers CD Fillingim RB. Sex differences in the perception of noxious experimental stimuli: a meta-analysis. Pain. 1998; 74:181-187. 32. Storey E. The nature of tooth movement. Am J Orthod Dentofacial Orthop. 1973; 63:292314. 33. Grieve WG, Johnson GK, Moore RN, Reinhard t RA, DuBois LM. Prostaglandin E (PGE) and interleukin-1B (IL-B) levels in gingiva l crevicular fluid dur ing human orthodontic tooth movement. Am J Orthod Dentofacial Orthop. 1994; 105:369-374. 34. Profiit WR, Fields HW. Contemporary Orthodontics. St. Louis, MO: Mosby; 2000. 35. Wong A, Reyonolds EC, West VC. The effect of acetylsalicylic acid on orthodontic tooth movement in the guinea pig. Am J Orthod Dentofacial Orthop. 1992; 102:360-365. 36. Chumbley AB, Tuncay OC. The effect of indomet hacin (an aspirin-like drug) on the rate of orthodontic tooth movement. Am J Orthod Dentofacial Orthop. 1986; 89:312-314. 37. Krykanides S, OBanion MK, Subtelny JD. Nonsteroidal anti-inflammatory drugs in orthodontic tooth movement: metalloprotei nase activity and collagen synthesis by endothelial cells. Am J Orthod Dentofacial Orthop. 2000; 118:203-209. 38. Walker JB, Buring SM. NSAID impairme nt of orthodontic tooth movement. The Annals of Pharmacotherapy. 2001; 35:113-115. 39. Tyrovola JB, Spyropoulos MN. Effects of drugs and systemic factors on orthodontic treatment. Quintessence International. 2001; 32:365-371.

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33 BIOGRAPHICAL SKETCH Shreena Patel was born in London, England in 1981. She grew up in Jacksonville, Fl, graduating from The Bolles School in 1998. She was subsequently accepted into the Honors Combined B.S./D.M.D. Program at the University of Florida. She received her B.S. in nutritional sciences in 2003, and her Doctor of Dental Me dicine degree from the University of Florida, College of Dentistry in 2005. Upon completion of her dental training, she continued her education at the University of Florida, earni ng a Master of Science with a certificate in orthodontics in May 2008.