<%BANNER%>

Dose Response of Ibuprofen Compared to Placebo on Post-Separator Placement Pain

Permanent Link: http://ufdc.ufl.edu/UFE0041785/00001

Material Information

Title: Dose Response of Ibuprofen Compared to Placebo on Post-Separator Placement Pain
Physical Description: 1 online resource (39 p.)
Language: english
Creator: Miller, Katherine
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: ibuprofen, nsaid, orthodontic, orthodontics, pain, placebo, separator, 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: DOSE RESPONSE OF IBUPROFEN COMPARED TO PLACEBO ON POST-SEPARATOR PLACEMENT PAIN Patients have long associated pain with dental work and orthodontics is no exception to this. With pain being a major drawback to orthodontic treatment, pain control is an increasingly important area for clinicians. The aims of this study were to investigate the efficacy and appropriate dosage of NSAIDs, specifically ibuprofen, as an analgesic for orthodontic pain control using orthodontic separators as a pain model, and also to assess the contribution of gender to the pain experience. Twenty subjects (13 female, 7 male) initiated the study to randomly receive one of three treatments: 400 mg ibuprofen, 200 mg ibuprofen or placebo. The dosing times were one hour prior to separator placement and every six hours thereafter for three days post separator placement. Prior to the first separator placement, a Chewing Efficiency Test and Visual Analog Scales (VAS) for pain experienced with the Chewing Efficiency Test and expected pain with separators were recorded in a pain diary. After the separators were placed, VAS for pain experienced upon placement and pain experienced after placement were completed and recorded in a pain diary which was kept for seven days. Subjects returned to the clinic after one week for separator removal. The subjects returned twice, separated by monthly intervals, to receive a different treatment drug with the same protocol. Out of the 20 subjects who initiated the study, 13 subjects (7 female, 6 male) completed the study and 7 subjects (6 female, 1 male) withdrew. By the end of the study, the 13 subjects who successfully completed the study received all three treatments medications. Out of the 7 subjects that withdrew; 1 received two treatment medications and 6 received one treatment medication. Based on the mixed model analyses (p < 0.05), orthodontic pain relief after separator placement was significant and greatest for the 400 mg dosage of ibuprofen compared to 200 mg of ibuprofen and placebo. No significant differences were detected between genders.
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 Katherine Miller.
Thesis: Thesis (M.S.)--University of Florida, 2010.
Local: Adviser: Wheeler, Timothy T.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041785:00001

Permanent Link: http://ufdc.ufl.edu/UFE0041785/00001

Material Information

Title: Dose Response of Ibuprofen Compared to Placebo on Post-Separator Placement Pain
Physical Description: 1 online resource (39 p.)
Language: english
Creator: Miller, Katherine
Publisher: University of Florida
Place of Publication: Gainesville, Fla.
Publication Date: 2010

Subjects

Subjects / Keywords: ibuprofen, nsaid, orthodontic, orthodontics, pain, placebo, separator, 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: DOSE RESPONSE OF IBUPROFEN COMPARED TO PLACEBO ON POST-SEPARATOR PLACEMENT PAIN Patients have long associated pain with dental work and orthodontics is no exception to this. With pain being a major drawback to orthodontic treatment, pain control is an increasingly important area for clinicians. The aims of this study were to investigate the efficacy and appropriate dosage of NSAIDs, specifically ibuprofen, as an analgesic for orthodontic pain control using orthodontic separators as a pain model, and also to assess the contribution of gender to the pain experience. Twenty subjects (13 female, 7 male) initiated the study to randomly receive one of three treatments: 400 mg ibuprofen, 200 mg ibuprofen or placebo. The dosing times were one hour prior to separator placement and every six hours thereafter for three days post separator placement. Prior to the first separator placement, a Chewing Efficiency Test and Visual Analog Scales (VAS) for pain experienced with the Chewing Efficiency Test and expected pain with separators were recorded in a pain diary. After the separators were placed, VAS for pain experienced upon placement and pain experienced after placement were completed and recorded in a pain diary which was kept for seven days. Subjects returned to the clinic after one week for separator removal. The subjects returned twice, separated by monthly intervals, to receive a different treatment drug with the same protocol. Out of the 20 subjects who initiated the study, 13 subjects (7 female, 6 male) completed the study and 7 subjects (6 female, 1 male) withdrew. By the end of the study, the 13 subjects who successfully completed the study received all three treatments medications. Out of the 7 subjects that withdrew; 1 received two treatment medications and 6 received one treatment medication. Based on the mixed model analyses (p < 0.05), orthodontic pain relief after separator placement was significant and greatest for the 400 mg dosage of ibuprofen compared to 200 mg of ibuprofen and placebo. No significant differences were detected between genders.
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 Katherine Miller.
Thesis: Thesis (M.S.)--University of Florida, 2010.
Local: Adviser: Wheeler, Timothy T.

Record Information

Source Institution: UFRGP
Rights Management: Applicable rights reserved.
Classification: lcc - LD1780 2010
System ID: UFE0041785:00001


This item has the following downloads:


Full Text

PAGE 1

DOSE RESPONSE OF IBUPROFEN COM PARED TO PLACEBO ON POSTSEPARATOR PLACEMENT PAIN By KATHERINE B. MILLER A THESIS PRESENTED TO THE GRADUATE SCHOOL OF THE UNIVERSITY OF FLORID A IN PARTIAL FULFILLMENT OF THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE UNIVERSITY OF FLORIDA 2010 1

PAGE 2

2010 Katherine B. Miller 2

PAGE 3

To my husband, Lane for his unending support and encouragement 3

PAGE 4

ACKNOWLEDGMENTS I would like to thank my research committ ee chair, Timothy T. Wheeler, D.M.D., Ph.D.; and committee members, Charles G. Widmer, D.D.S., M.S.; and Susan P. McGorray, Ph.D. for th eir mentoring and guidance. I would also like to thank Marie Taylor for her assistance with the study. Finally, I would like to acknowledge the Southern Association of Orthodontists grant and the Univer sity of Florida Graduate Student Council grant for financial support. 4

PAGE 5

TABLE OF CONTENTS page ACKNOWLEDGMENTS ..................................................................................................4 LIST OF TABLES ............................................................................................................6 LIST OF FIGURES ..........................................................................................................7 LIST OF ABBREVIATIONS .............................................................................................8 ABSTRACT .....................................................................................................................9 CHAPTER 1 INTRODUCTION ....................................................................................................11 2 MATERIALS AND METHODS ................................................................................13 Sample Population ..................................................................................................13 Inclusion and Exclusion Criteria .......................................................................13 Pain Model ..............................................................................................................13 Statistical Analysis ..................................................................................................16 3 RESULTS ...............................................................................................................19 4 DISCUSSION .........................................................................................................25 5 CONCLUSIONS .....................................................................................................35 LIST OF REFERENCES ...............................................................................................36 BIOGRAPHICAL SKETCH ............................................................................................39 5

PAGE 6

LIST OF TABLES Table page 2-1 Day 1: Treatment and dosing timelin e for all subjects to be repeated three times at monthly intervals. ..................................................................................18 3-1 Race and gender demographics .........................................................................21 3-2 Descriptive statistical variables ...........................................................................21 3-3 Baseline characteristics by treatment group .......................................................22 6

PAGE 7

LIST OF FIGURES Figure page 3-1 Mean cumulative VAS pain scores for all treatment medications at each time point. = p < 0.05 for IBU 0 vs. IBU 200. = p < 0.05 for IBU 0 vs IBU 400. = p < 0.05 for IBU 200 vs IBU 400. ..................................................................23 3-2 Mean cumulative VAS almond pain sco res for all treatment medications at each time point. = p < 0.05 for IBU 0 vs. IBU 200. = p < 0.05 for IBU 0 vs. IBU 400. = p < 0. 05 for IBU 200 vs. IBU 400. ...........................................23 3-3 Mean chewing efficiency scores for all treatment medications at each time point. No statistically significant di fferences among groups was identified (p > 0.05). ...............................................................................................................24 7

PAGE 8

LIST OF ABBREVIATIONS IBU 0 placebo IBU 200 200 mg ibuprofen IBU 400 400 mg ibuprofen IDS investigational drug service IL-1B interleukin 1-beta NSAID non steroidal anti-inflammatory drug PGE2 prostaglandin E2 SP substance P s.d. standard deviation VAS visual analog scale 8

PAGE 9

Abstract of Thesis Pres ented to the Graduate School of the University of Florida in Partial Fulf illment of the Requirements for t he Degree of Master of Science DOSE RESPONSE OF IBUPROFEN COM PARED TO PLACEBO ON POSTSEPARATOR PLACEMENT PAIN By Katherine B. Miller May 2010 Chair: Timothy T. Wheeler Major: Dental Sciences Patients have long associated pain with dental work and orthodontics is no exception to this. With pain being a ma jor drawback to orthodont ic treatment, pain control is an increasingly import ant area for clinicians. The ai ms of this st udy were to investigate the efficacy and appropr iate dosage of NSAIDs, spec ifically ibuprofen, as an analgesic for orthodontic pain control using orthodontic separators as a pain model, and also to assess the contribution of gender to the pain experience. Twenty subjects (13 female, 7 male) initiated the study to rando mly receive one of three treatments: 400 mg ibuprofen, 200 mg ibuprofen or placebo. The dosing times were one hour prior to separator placement and every six hours t hereafter for three days post separator placement. Prior to the firs t separator placement, a Chewing Efficiency Test and Visual Analog Scales (VAS) for pain experienced with the Chewing Efficiency Test and expected pain with separators were recorded in a pain diary. After the separators were placed, VAS for pain experienced upon placement and pain experienced after placement were completed and recorded in a pai n diary which was kept for seven days. Subjects returned to the clinic after one w eek for separator removal. The subjects returned twice, separated by monthly intervals, to receive a different treatment drug with 9

PAGE 10

10 the same protocol. Out of the 20 subjects who initiated the study, 13 subjects (7 female, 6 male) completed the study and 7 s ubjects (6 female, 1 male) withdrew. By the end of the study, the 13 subjects who succe ssfully completed the study received all three treatments medications. Out of the 7 subjects that withdrew; 1 received two treatment medications and 6 received one treatment medica tion. Based on the mixed model analyses (p < 0.05), orthodontic pain relief after separator placement was significant and greatest for the 400 mg dos age of ibuprofen compared to 200 mg of ibuprofen and placebo. No significant di fferences were detected between genders.

PAGE 11

CHAPTER 1 INTRODUCTION Pain is among the most cited negative effe cts of orthodontic treatment and is a major concern to patients.1 2 Orthodontic therapy is reported to be painful for 90% of patients, with some 30% contemplating termi nating their treatment early because of discomfort.3 With this in mind, pain control is an area of interest for clinicians. Ibuprofen is a common over the counter non-steroidal anti-inflammatory drug (NSAID) that is regularly taken by patients with pain. An NSAID such as ibuprofen has been found to be effective in reducing postopera tive pain when pain is a result of tissue damage and inflammation.4 One study comparing t he effect of preoperative vs. postoperative ibuprofen therapy on ort hodontic pain revealed that preoperative ibuprofen decreased pain that was experienced 2 hours after separator placement and at bedtime.5 Also, patients who had taken both preoperative and postoperative ibuprofen doses had lower pain scores altogether. A second study by Law et al.6 found similar results that revealed patients who took ibuprofen pr eoperatively had significantly less pain while chewing 2 hours after treatment than did patients who took ibuprofen postoperatively or placebo. While these studi es identified ibuprofen as being effective in reducing postoperative ort hodontic pain, they did not address the appropriate dosage of ibuprofen to prescribe orthodontic patients seeking pain relief. Patients who consume ibuprofen for pain relief have the potential of developing negative side affects including ga strointestinal intolerance 6 and inhibition of tooth movement.6, 7 Therefore it would be important to know the appropriate dosage of ibuprofen necessary to alleviate orthodontic pain. 11

PAGE 12

12 The purpose of this study was to investi gate the efficacy of two dosage regimens of ibuprofen (200 or 400 mg th ree times per day for three days) compared to placebo to determine which treatment regim en is most effective in cont rolling orthodontic pain over a seven day period using orthodont ic separators as a pain model. In addition, potential gender differences were evaluated.

PAGE 13

CHAPTER 2 MATERIALS AND METHODS Sample Population Twenty non-orthodontic subjects (7 male, 13 female) presen ted to the University of Florida Orthodontic Clinic for initiation of the study. Prior to separ ator placement, each subject had to meet the follo wing inclusion criteria: Inclusion and Exclusion Criteria The subject must be between the ages of 18 30. The subject must not be pregnant. If the subject is a female of child-b earing potential, she must consent to a pregnancy test. The subject must have second premolars, first molars, and se cond molars that are in contact, therefore requi ring the placement of two separators in each of four quadrants. The subject must not be currently ta king any steroidal or non-steroidal pain medications or any other anti-pain drugs. The subject must have no contraindicati ons or adverse reactions to ibuprofen. The subject must have no contraindica tions or adverse reactions to nuts. The subject must give written informed consent for participation in the study. The subject must not need antibiotic pr ophylaxis prior to dental treatment. Pain Model Two elastic separators were placed in each quadrant to induce pain. As shown in Figure 2-1, each subject was to randomly receive one of three possible treatment medications one week per month over a three month time span: 200 mg ibuprofen, 400 mg ibuprofen, or placebo. Twenty subjects were recruited to in itiate the study while only 13 subjects successfully completed the study. 13

PAGE 14

One hour prior to separator placemen t, each subject was administered their specific randomized treatment medication. After separator placement, subjects self administered the treatment medication for the first three days, every six hours (three times a day), with food (or at mealtime). The subjects were contacted via a phone call 10 minutes before each dosing time reminding them to take thei r medication. The dosing times were as follows: D1 = drug one hour prior to separator placement D2 D9 = drug every 6 hours (tid) after separator placement for 3 days (Day 1 Day 3). (Table 2-1) The Investigational Drug Service (IDS) at Shands Hospital Pharmacy formulated all of the treatment medications to ensure a double-blind research design. The IDS reencapsulated each treatment medication into tw o capsules for each dosing time point. The IDS dispensed the tablets to the researc her; the capsules were then dispensed to the subject accordingly and the subject took bo th capsules at each dosing time point. The order of the treat ment medications was randomized per round. Prior to time of separator placement (Tx), the following instruments were completed by all subjects: Magnitude Estimations:8 subjects were asked to identify mild, moderate and intense pain ranges using a 100 mm Visual Analog Scal e (VAS) with anchors of no pain at all (0mm) and worst pain imaginable (100 mm).9 Assessment of Expected Pain: subjects were asked to rate their expectation of pain as a result of separator placem ent prior to separator plac ement using a 100 mm Visual Analog Scale. 14

PAGE 15

Chewing Efficiency Test10: each subject 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 almond. Subjects then rated their pain as a consequence of chewing the almond on a VAS for both right and left sides. Pregnancy test for all female subjects The results of the pregnancy test had to be negative for the subject to continue as a participant in this study. Separators were placed after administrat ion of the above test s (T0) and one hour after the first drug dosing (D1). Two separat ors (Orthotec, P/N 480302) were placed in each quadrant mesial and distal to the 1st mola r. Each separator was placed under the contact for all subjects. Pain upon separat or placement was recorded on the VAS in their pain diary. Subjects recorded their pain intensity while chewing, biting and fitting their back teeth together on a VAS in the pain diary at 3 hours post separator placement (T1), 6 hours post separator placement (T2), at bedtime after separator placement (T3), and upon awakening and bedtime (Day 2 Day 7, T4-T15) (Table 2-1). To complete the chewing efficiency test and the associated pain recordings, the subjects were given bagged almonds separated for each time point and enclosed in a standard dental sterilization pouch for transport. At bedtime (T 3, T5, T7, T9, T11, T13, T15), after the chewing, biting and fitti ng back teeth together VAS pain scales were completed, each subject self administered the chewing efficiency test by chewing a bagged almond and assessing pain using a VAS loca ted within the pain diary. Each subject returned the completed pain diary and the chewed bags of almonds to the next appointment, one week later, at which time separators were removed. 15

PAGE 16

One investigator (K.M.) measured the VAS ratings and recorded the data for statistical analysis. A calibration procedure of the investigator was conducted prior to all measurements. The calibration was as follows: 10 subjects Day 2 VAS were measured, then re-measured twic e more for a total of thr ee separate measurements. These measurements were carried out ov er a three week period, with each measurement being separated by one week Measurements were made using an electronic caliper with an accuracy of 0.01 mm. Analysis of the chewed almonds was as follows: the whole sample was weighed, the sample was then sifted using a 1 mm2 mesh, and the separated sample was then weighed. The chewing efficiency was dete rmined to be the percent of the original sample that passed through the sieve. Th is process was measured in duplicate, and the values averaged for accuracy. One month later the subjects returned to th e clinic to receive a different treatment drug with the same dosing and assessment pr otocol. After completing the second treatment regimen, the subjects returned one month later to complete the third and final treatment regimen with the same dosing and assessment protocol. At the end of the three months, each subject who successfully completed the study received all three treatment medications. The medical history was updated and el igibility via inclusion and exclusion criteria was confirmed at each visit. Statistical Analysis Demographic variables including race, age, sex, height and weight were recorded for each participant at each period and summa rized using descriptive statistics. A linear mixed modeling approach was us ed to assess differences between treatment groups for the outcome s of interest. Mi xed models are able to account for the 16

PAGE 17

structure of the data, with multiple observations over time within each subject, and multiple treatments per subjec t. A first-order autoregressi ve correlation structure was used to address the repeated pain measures over the course of a treatment. This allows time points closer in time to be more highly correlated. Initial models include drug, day number, baseline value (if app licable), period, carryover and drug x day number interacti on. Differences by day number between drugs were assessed using a model that included the interaction terms, drug x day number. Carryover effects and period effects we re also analyzed in the initial models. A carryover effect is an effect from the pr evious round influencing the subject during the present round, regardless of what treatm ent medication the s ubject was currently receiving. A period effect would be if the pain decreased over periods, regardless of the treatment medication the subjec ts received or were receiving. If period and carryover effects were not significant, they were re moved from the model. For all treatment comparisons, p-values are based on mixed m odel results, unless otherwise noted, and a p-value of less that 0.05 is considered statistically significant. As described previously, each subject wa s asked to indicate mild, moderate and intense pain ranges on a 100 mm VAS. This wa s conducted at the initiation of each round of the study for each subj ect. The VAS pain rating data for each round were then standardized to that rounds particular ma gnitude estimations that had been completed at the initiation of the round. For example, a participant may have indicated that the cut point between mild and moder ate pain was 20, and the cut point between moderate and intense pain was 60. Then if the subject rated subsequent pain as 60, this would be standardized to 66.7. Similarly, a sco re of 40 would be st andardized as 50. 17

PAGE 18

Table 2-1. Day 1: Treatment and dosing ti meline for all subjects to be repeated three times at monthly intervals. To D1 Tx T1 D2 T2 D3 T3 400 mg ibuprofen 400 mg ibuprofen 400 mg ibuprofen 200 mg ibuprofen 200 mg ibuprofen 200 mg ibuprofen Record height/ weight, Magnitude Estimations, Expected Pain Rating, Chewing Efficiency and Experienced Pain Rating Placebo Experienced Pain Rating (VAS) Pain Diary (Sensory VAS scoring) Placebo Pain Diary (Sensory VAS scoring) Placebo Pain Diary, Chewing Efficiency and Experienced pain -1 hr -1 hr Separator Placement +3 hr +6 hr +6 hr +12 hr Bed Time 18

PAGE 19

CHAPTER 3 RESULTS The study sample consisted of 13 female s (65%) and 7 males ( 35%). The race, sex, age, height and weight demographic statis tics are described in t ables 3-1 and 3-2. Out of the 20 subjects who initiated the study 13 subjects (7 female, 6 male) completed the study. Data from thes e subjects were analyzed and included in the results, along with data from the 7 subjects (6 female, 1 male) that withdrew from the study. Withdrawal did not differ by sex (Fisher exac t test, p=0.33). By th e end of the study, 13 of the 20 subjects received all three treatme nt medications, 1 received two treatment medications, and six received one treatment medication. Baseline characteristics by treatment gr oup for expected pain prior to separator placement, almond chewing pain prior to se parator placement, chewing efficiencies prior to separator placement and experienced pain at separator placement are listed in Table 3-3. No statistically significant di fferences were found between treatment groups in standardized expected pain prior to separ ator placement (p = 0.52), between the treatment groups in standardized VAS almond pai n scores prior to separator placement (p = 0.72) or between the tr eatment groups in standardized chewing efficiencies prior to separator placement (p = 0.805) No statistically signif icant differences were found between placebo and 200 mg ibuprofen (p = 0.10) or 200 mg ibuprofen and 400 mg ibuprofen (p = 0.09) when assessing standardi zed pain at the time of separator placement. However, a statistically signi ficant difference was found between placebo and 400 mg ibuprofen (p = 0.0017) treatment groups when assessing standardized pain at the time of separ ator placement. 19

PAGE 20

In Figure 3-1, Day 0 AM represents t he time point three hours after separator placement and Day 7 AM represents the time poi nt at which separators were removed. The time point three hours after separator pl acement was chosen as Day 0 AM since it was the first time point that included all of the VAS pain ratings (chewing, biting and fitting back teeth together). As shown in Figur e 3-1, subjects reported statistically lower levels of pain while taking 400 mg ibupr ofen compared to placebo for the three days prescribed. This statistically significant di fference is also seen for the remaining days of the week (except Day 4, PM and Day 5, AM ), after the treatment medication had been stopped. Also a statistically significant difference in pain levels between 200mg and 400mg ibuprofen is shown at Day 1, Day 2 AM, Day 4 AM and Day 6. In comparison of the placebo and 200mg ibuprofen treatment medications, the onl y statistically significant differences noted in pain levels were at Da y 0 PM and Day 2 PM. Subjects reported having higher mean pain scores for these tw o treatment groups co mpared to the 400mg ibuprofen treatment group. Differences were also noted in reported pain based on the time of day. For all three treatment medications, subjects r eported having higher mean pain scores in the evening (PM) versus the morning (AM) through the three days of dosing. Mixed model estimates indicate the standardized pain score is approximately 8 points lower in the morning (coefficient estimate -7,80, s.d. 2.66, p=0.0034). Mean pain appears to peak in the placebo group around the second day of dosing, then shows a progressive decrease for each time point until s eparators are removed at Day 7 AM. The VAS almond pain scores are shown in Fi gure 3-2. Day 0 represents day of separator placement, Day 7 represents day of separator removal. Subjects reported the 20

PAGE 21

least amount of mean pain when chewing the almond while taking 400mg ibuprofen. A statistically significant difference in alm ond chewing pain levels between placebo and 400mg ibuprofen is seen at Days 0-3 and Day 7. A statistically significant difference in almond chewing pain levels is also seen between 200mg ibuprofen and 400mg ibuprofen at Days 1 and 6; and between pl acebo and 200mg ibupr ofen at Day 0. Chewing efficiencies are shown in Figur e 3-3, with Day 0 representing day of separator placement and Day 7 representing day of separator removal. As shown in Figure 3-3, no treatment medication was found to correlate with a statistically significant higher chewing efficiency. Therefore, che wing efficiency results did not correlate with treatment medication/pain results. No statistically significant differences were found between gender (p=0.87) for the VAS pain ratings or chewing efficiencies. There was also no evidence of a carryover (p=0.95) or period (p=0.48) effect. Table 3-1. Race and gender demographics Frequency Percentage Female 13 65 Male 7 35 White 13 65 Black 1 5 Hispanic 2 10 Asian 2 10 Other 2 10 Table 3-2. Descriptive statistical variables Median Mean Std Dev Age (yrs) 27.2 27.1 3.1 Height (in) 67.0 66.2 3.2 Weight (lbs) 140.0 143.1 22.5 21

PAGE 22

Table 3-3. Baseline characteristics by treatment group Treatment Variable Mean Lower 95% Confidence Level for Mean Upper 95% Confidence Level for Mean IBU 0 Expected prior 39.59 24.21 54.97 Chew prior 3.61 0.76 6.45 Chew Efficiency prior 49.50 37.34 61.66 Experienced 52.51 42.50 62.53 IBU 200 Expected prior 42.39 31.10 53.69 Chew prior 5.40 0.25 10.56 Chew Efficiency prior 46.33 33.33 59.34 Experienced 43.09 34.42 51.76 IBU 400 Expected prior 35.55 26.46 44.64 Chew prior 2.88 1.59 4.18 Chew Efficiency prior 45.83 33.37 58.30 Experienced 35.42 24.33 46.50 p-value Variable IBU 0 vs IBU 200 IBU 200 vs IBU 400 IBU 0 vs IBU 400 0.52 Expected prior 0.72 Chew prior 0.805 Chew Efficiency prior 0.0064 Experienced 0.10 0.09 0.0017 Expected prior = VAS expected pain prior to separator placement Chew prior = VAS almond chewing pai n prior to separator placement Chew Efficiency prior = Chewing effi ciency prior to separator placement Experienced = Experienced pai n at separator placement = p < 0.05 (statistical significance) 22

PAGE 23

Figure 3-1. Mean cumulative VAS pain score s for all treatment medications at each time point. = p < 0.05 for IBU 0 vs. IBU 200. = p < 0.05 for IBU 0 vs IBU 400. = p < 0.05 for IBU 200 vs IBU 400. Figure 3-2. Mean cumulative VAS almond pain scores for all treatment medications at each time point. = p < 0.05 for IBU 0 vs. IBU 200. = p < 0.05 for IBU 0 vs. IBU 400. = p < 0.05 for IBU 200 vs. IBU 400. 23

PAGE 24

24 Figure 3-3. Mean chewing efficiency scores fo r all treatment medications at each time point. No statistically significant differences among groups was identified (p > 0.05).

PAGE 25

CHAPTER 4 DISCUSSION As stated previously, pain is a majo r concern for patients considering orthodontic treatment. One survey rated pain as the greatest dislike during treatment and fourth among major fear s and apprehensions prior to orthodontic treatment.11 This study was designed as a prospective, double blind, complete block crossover clinical trial that compared the efficacy of two different doses of ibuprofen or placebo in reducing the inciden ce and severity of orthodontic pain. Ibuprofen was selected as the drug of choice after reviewing several articles that investigated ibuprofen versus other ov er the counter analges ics. One study compared ibuprofen to aspirin and plac ebo in controlling orthodontic pain after initial archwire or separ ator placement and found that the ibuprofen group perceived significantly less discomfort than did the aspiri n group and concluded that ibuprofen is the preferred analgesic in the treatment of pain associated with orthodontic adjustments.12 A second study investigated ibuprofen, acetaminophen, naproxen sodium and placebo on pain experienced with orthodontic separators. The investigators found that ibupr ofen given 1 hr prior to separator placement, and 3 and 7 hrs following placement, reduces postseparator placement pain compared with placebo, and that naproxen sodium and acetaminophen do not signific antly differ from placebo.13 Since ibuprofen has been identified as the drug of choice in treating orthodontic pain, the current study was conducted to identify the specific dosage and schedule of ibuprofen 25

PAGE 26

that is necessary to prescribe orthodontic patients in treatment of orthodontic pain. As stated previously, twenty subjects in itiated the current study while only 13 subjects successfully completed the study. The 7 subjects that did not complete the study cited pain as being t he reason for dropping out. Out of these 7 subjects, 6 were female and 1 was male From these resu lts it would appear that females were more likely to withdraw from the study compared to males, but as reported earlier this was not the case since withdrawal did not differ by sex (Fisher exact test, p=0.33). The fact t hat females make up 65% of the initial study sample could explain the female withdrawal trend noted; more females would be expected to withdraw since more females initiated the study. The data analyzed included the 13 subjects who comp leted the study and the 7 subjects who withdrew from the study. Based on the results, pain relief following separator placement was significantly related to the treatm ent medication. When dosed with 400 mg ibuprofen one hour prior to separator placement, subjects reported a statistically greater pain relief at immediate time of separator placement versus placebo. Subjects also reported the greatest mean pain relief after separator placement while taking 400 mg ibuprofen every six hours after a meal. While in some patients 200 mg ibuprofen mi ght be adequate, it would be difficult to determine which patients this would include. To ex trapolate this information to our clinical practice, practitioners have two choices of treatment for reduction of orthodontic pain experienced after each appointment. Pr actitioners could start by prescribing 26

PAGE 27

patients 200 mg ibuprofen three times a day for three days for orthodontic pain relief, then increase the dosage to 400 mg ibuprofen three times a day for those patients who need greater pain relief. A nother option would be to prescribe patients 400 mg ibuprofen three times a day for three days for orthodontic pain relief if a 400 mg dose of ibuprofen is not contraindicated due to a medical history that would prohibit prescribi ng aspirin or NSAIDS. Another finding from this study is the difference in pain reported by subjects based on the time of day. Subjects reported generally more pain in the evening than in the morning through the three da ys of dosing for all three treatment medications. Pain has been found to ex hibit a pattern, with evening and nights showing the highest scores of pain.14 One study proposed that the mechanism of pain involves an inflammatory respons e as a result of tissue damage, rather than a compressive force, which would pr esumably result in greater pain levels immediately after the separ ator placement appointment.6 This diurnal variation could be explained by a natural progression of pain after a traumatic experience like separator placement, which initiates an inflammatory response. There is no doubt that or thodontic pain is part of an inflammatory reaction causing changes in blood flow foll owing orthodontic tooth movement.15 The inflammation caused by orthodontic force application stimulates the release of various biochemical mediators such as substance P, histamine, enkephalin, dopamine, serotonin, glycine, glut amate gamma-amino butyric acid, prostaglandins, leukotrienes and cytokines.15 Inflammatory mediators such as interleukin 1B (IL-1B), substance P (SP), and prostaglandin E2 (PGE2) increase 27

PAGE 28

significantly during inflammation. Pros taglandins enhance the transmission of painful stimuli and have been shown to cause hyperalgesia; in explanation prostaglandins sensitize the peripheral pain receptors to send a pain signal to the central nervous system ( CNS). One study exami ned the presence of these inflammatory mediators in gingival crevicular fluid after the placement of separators.16 After day 1, all 3 substances increased to the highest percentage at treatment sites of all tested occasions versus the controls. This shows that IL1B, SP and PGE2 were expressed during initial tooth movement in sufficient amounts. Another study of the same sample examined the gingival crevicular fluid of the tension versus compressi on sides of a tooth following separator placement.17 The authors found that IL-1B, SP and PGE2 were increased by orthodontic forces that cause bone rem odeling/inflammation, and their levels were significantly greater in the tension sites than in the compression sites. These results indicate that the applicati on of mechanical force, even a light force induced by a separator, provokes an inflammatory reaction which is reflected by changes in the gingival crevicular fluid co mposition. The natural progression of this inflammatory reaction could explain why more pain was reported by subjects in the evening. Since orthodontic appointments occur during the day, pain would tend to peak in the evening, after the inflammatory pathways had time to initiate and proceed. During the days following an orthodontic appointment the inflammatory response will be proceeding at a constant rate and therefore would not explain the diurnal variation that is noted in th is study during the remaining days of the 28

PAGE 29

week. An explanation for the diurnal variation noted th roughout the week in this study could be explained by hormonal c ontrol of the body. Cortisol is a corticosteroid hormone produced by the co rtex of the adrenal gland. Cortisol is referred to as the stress hormone and is involved in response to stress and anxiety, and reduces immune responses (inflammation). Hydrocortisone is a well-known synthetic form of cortisol and is used for its anti-inflammatory effects to treat a variety of conditions, including rheumatoid arthriti s. The amount of cortisol in the blood undergoes a diurnal variation with the highest levels present in the early morning and lowest levels present in the late evening.18 Cortisols natural anti-inflammatory effe cts could be causing the diurnal variation seen in orthodontic pain days after the procedure takes place. The duration of pain after orthodontic treatment has been initiated has also been investigated. The consensus report ed is that pain begins a few hours after initiation of an orthodontic force and lasts approximately 5 7 days; after day 5 only mild discomfort was reported by patients. 19 20 Our results seem to agree with this finding. In our study we obs erved mean pain to peak in the placebo group around Day 2 PM and then progressive ly decrease until separator removal at Day 7 AM. Our findings also seem to agree with clinically controlled trials by Ngan 12, 21 and by Giannopoulou which shows discomfort associated with separator placement, which usually star ts within 4 hours after insertion and peaks at 24 hours after insertion, decreases to pre-placement level within 7 days. On the other hand, our findings differ ed in that observed mean pain peaked around Day 2 PM, not 24 hours after separ ator placement. Since mean pain 16 29

PAGE 30

peaks around Day 2 PM, our protocol to adm inister the treatment medication for only three days post separator placement is justified. Pain relief following almond chewing was also significantly related to the treatment medication. Subjects repor ted the greatest mean pain relief while chewing the almond when taking 400mg ibup rofen as prescribed. Also, this finding agrees with the previously menti oned result of subjects reporting the greatest mean pain relief while taking 400 mg ibuprofen as prescribed for orthodontic pain. Therefore, to re duce orthodontic pain experienced during chewing, 400mg ibuprofen should be prescri bed. Again, in some patients 200mg of ibuprofen might be adequate bu t these patients would be difficult to identify. Since no statistically significant diff erences were found between the treatment groups for VAS almond pain scores prior to separator placement, each treatment medication was determined to be equally e ffective in treating almond chewing pain prior to separator placement. No correlation was noted between chewing efficiencies and treatment medication. Since no statistical signific ance was found, all treatment medications are treated as being equally effective in leading to good chewing efficiencies. Also, no statistically significant differences were found between the treatment groups for expected pain prior to separat or placement. Based on these results there was no evidence of a carryover effe ct or period effect. As previously described, carryover and period effect s may influence the subjects pain perception and therefore scoring of the VAS. In a carryover effect, if the subject experienced what they perceived as a painful experience in the previous round of 30

PAGE 31

the study, that experience could negatively affect the s ubject in the next round of the study and influence their scoring of the VAS. A period effect would be if pain decreased over periods, regardless of the treatment medication the subjects received. In this study, period 1 = first round of the study with the first treatment medication, period 2 = second round with the second treatment medication, and period 3 = third round with the third treatment medication. After evaluation of the data, these effects were found to not be a fa ctor in influencing the subjects in any way. Pain perception can be dependent upon va riables such as age, gender, individual pain threshold, the magnit ude and duration of the force applied, present emotional state and stress, cult ural differences and previous pain experiences.21, 22 Traditionally, it is believed that females are fragile and sensitive to pain, while males are mo re stoic and can tolerate more pain.23 Conflicting results have been reported with some showing that males are more willing to tolerate pain than females, but others report no differences between males and females in reporting the feeling of pain with respect to threshold.24 Scheurer et al.25 found significant differences in response of pain between the sexes. Girls reported significantly greater pain intensity and consumed significantly more analgesics than males. In contradict ion to this, Jones et al.,26 and Erdinc et al.27 both reported no significant differences between sexes in perception of pain during or thodontic treatment. Likewise, the current study did not detect any statistical differences found in pain perception based on gender differences. 31

PAGE 32

As stated previously, ibuprofen was selected as the drug of choice after several studies identified it as being the best over the counter analgesic to successfully treat orthodontic pain.5,12,13 The drawbacks to ibuprofen therapy in controlling orthodontic pain are the possibl e side effects and potential to inhibit tooth movement. The most common side e ffect of ibuprofen is gastrointestinal intolerance. It has been reported that gastr ointestinal side effects occur in up to 15% of patients taking ibuprofen.6 Ibuprofen also reversibly alters platelet function and prolongs bleeding time. Thes e side effects could be significant if multiple doses are taken by the patient over an extended time period. That is why in this study, the subjects were pr escribed over the counter doses and not an amount that would be prescribed for a c linical condition or that may exceed the clinically recommended limit. As described previously, when adequate mechanical forces are applied to teeth, an acute inflammatory response occurs in the periodontal tissues and many inflammatory mediators are released, including prostaglandins (more specifically PGE2). Prostaglandins are thought to be mediators of tooth movement by altering the activity or the numbers of osteoclasts or osteoclast-like cells.17, 28 Since NSAIDs like Ibuprofen are inhi bitors of prostaglandins, it is reasonable to expect that they would inhibit or delay orthodontic tooth movement.6,7 Administering 2400-3200mg ibuprofen for 2 weeks will reach antiinflammatory levels. In the current st udy, we administered at the most 1200 mg/day for three days. Therefore in this study, drug levels did not reach the antiinflammatory levels and therefore should not inhibit tooth movement. 32

PAGE 33

Since ibuprofen serum levels do not r each anti-inflammatory levels, the analgesic effects of ibuprofen are largel y due to a central-acting mechanism of action. One study showed that spi nal administration of NSAIDs block hyperalgesia induced by the activati on of spinal glutamate receptors.29 Another study which administered N methyl D aspar tate (NMDA) to invoke a centrally acting hyperalgesia in rats (biting, scr atching, licking) showed that this pain response was reduced when ibuprofen was administered intra-peritoneally. NMDA is an excitatory amino ac id receptor agonist in the CNS.30 Ibuprofen in this study was shown to reduce the peak response and duration of the centrally acting hyperalgesia response elicited by NMDA injections. These findings demonstrate that the analgesic effects of NSAIDs can be dissociated from their anti-inflammatory actions. When determining statistical power, an impo rtant point to consider is study design. Previous studies on managing orthodontic pain with analgesics have been parallel arm, in which each subject receives only one treatment. The current study was designed to be a complete block crossover design, with all subjects receiving all three of the possibl e treatments. Howeve r, not all subjects successfully completed the study, but t heir data was included. While not all participants completed the study, most received more than one treatment medication, which still has better statistica l power than a parallel arm study. With the incomplete block study design, much of the between-subject variability can be eliminated since most of the subjects receiv ed all three treatment medications. 33

PAGE 34

There are limitations to this study. We experienced a high drop-out rate for subjects which led to a small sample si ze. Based on estimates from our data for standardized VAS pain scores, and assuming 13 subjects with complete information, we had 0.80 power (two-sided te st, level of significance 0.05, s.d. 90 for within subject drug differences) to detect a difference of 76 between two drug doses. In a similar parallel arm study (s.d. 109 for each dose, based on estimates from our data), 68 subjects would be required to duplicate the power and detectable difference of our study. Also, each subjects raw data for each round was normalized to their magnitude es timation ratings for that specific round, which minimized within and between-s ubject variability. The inclusion of data from one subject who required re scue medication during one round of the study is another limitation. Subjects were to contact the Princi pal Investigator if rescue medication was needed, and the resc ue medication prescribed was 650 mg acetaminophen. Another potential limitation is non compliance with the protocol. Even though subjects received a reminder phone call to self administer their medication, they may not have self-administered on time. Also, subjects eat meals at different times and go to bed at di fferent times, ther efore complete the pain diary at different times which coul d affect pain scores. The age range of subjects in this study wa s between 18 30 years, but many individuals receiving orthodontics are younger. While there is no reason to think that the current information cannot be applied to other age groups, those studies need to be done for confirmation. 34

PAGE 35

CHAPTER 5 CONCLUSIONS Previous studies investigating pain re lief following ortho dontic appointments identified ibuprofen as being the analgesic of choice, but did not identify the proper dosing schedule of ibuprofen to be pr escribed to orthodontic patients. In this study, 400 mg ibuprofen adminis tered one hour prior to orthodontic appointments and subsequently th ree times a day for three days after orthodontic appointments was found to statistically reduce pain from chewing, biting and fitting back teeth together in an orthodontic tooth separator m odel compared to 200 mg ibuprofen and placebo. Fr om these findings, 400 mg ibuprofen administered one hour prior to orthodontic appointments and subsequently three times a day for three days after ort hodontic appointments is suggested as the appropriate dosing schedule to be prescr ibed to patients seeking orthodontic pain relief. 35

PAGE 36

LIST OF REFERENCES 1. Oliver RG, Knapman YM. Attitudes to orthodontic treatment. British Journal of Orthodontics 1985;12:179-188. 2. Asham AA, Southard KA. Orthodont ic pain. American Journal of Dentofacial Orthopedics 2004;125:18A. 3. Lew KKK. Attitudes and perception of adults towa rd orthodontic treatment in an Asian community. Community Dentistry and Oral Epidemiology 1993;21:31-35. 4. Frame JW, Evans CR, Flaum GR, Langford R, Rout PG. A comparison of Ibuprofen and dihydrocodeine in relie ving pain following wisdom teeth removal. British Dental Journal 1989;166(4):121-4. 5. Bernhardt MK, Southard KA, Batterson KD, Logan HL, Baker KA, Jakobson JR. The effect of pree mptive and/or postoperative ibuprofen therapy for orthodontic pain. Am erican Journal of Orthodontics and Dentofacial Ort hopedics 2001;120:20-27. 6. Law SLS, Southard KA, Law AS, Logan HL, Jakobsen JR. An evaluation of preoperative ibuprofen for treatment of pain associated with orthodontic separator placement. American Jour nal of Orthodontics and Dentofacial Orthopedics 2000; 118:629-635. 7. Walker JB, Buring SM. NSAID im pairment of tooth movement. The Annals of Pharmaco therapy 2001;35:113-115. 8. Rainville P, Feine JS, Bushnell MC, Duncan GH. A psychophysical comparison of sensory and affective responses to four modalities of experimental pain. Somatosens ory and Motor Research. 1992;9(4):26577. 9. Seymour RA, Simpson JM, Charlton JE, Phillips ME. An evaluation of length and end-phrase of visual analog ue scales in dental pain. Pain 1985;21:177-185. 10. Al-Ali F, Heath MR, Wright PS. Simplified method of estimating masticatory performance. Journal of Oral Rehabilitation. 1999;26:678683. 11. OConnor PJ. Patients perceptions before, during, and after orthodontic treatment. Journal of Clini cal Orthodontics 2000;34:591-592. 36

PAGE 37

12. Ngan P, Wilson S, Shanfeld J, Amin i H. The effect of ibuprofen on the level of discomfort in patients undergoing orthodontic treatment. American Journal of Orthodontics and Dentof acial Orthopedics 1994;106:88-95. 13. Patel S, McGorray S, Yezierski R, Fillingim R, Logan H, Wheeler TT. Effects of analgesics on preand postseparator pai n. Masters thesis University of Florida 2008. 14. Sergl HG, Klages U, Zentner A. Pain and discomfort during orthodontic treatment: causative factors and effects on compliance. American Journal of Orthodontics and Dentofac ial Orthopedics 1998;114:684-691. 15. Krishnan V. Orthodontic pain: from cause to management a review. European Journal of Orthodontics 2007;29:170-179. 16. Giannopoulou C, Dudic A, Kiliaridis S. Pain discomfort and crevicular fluid changes induced by orthodontic elastic separators in children. The Journal of Pain 2006;7:367-376. 17. Dudic A, Kiliaridis S, Mombelli A, Giannopoulou C. Composition changes in gingival crevicular fluid dur ing orthodontic tooth movement: comparisions between tension and compression sides. European Journal of Oral Science 2006;114:416-412. 18. DeWeerth D, Zijl RH, Buitelaar JK Development of cortisol circadian rhythm in infancy. Early Hu man Development 2003;73(1-2):39-52. 19. Jones M. An investigation into t he initial discomfort caused by placement of an archwire. European Journa l of Orthodontics 1984;6:48-54. 20. Jones M, Richmond S. Initial toot h movement: force application and pain a relationship? American Jour nal of Orthodontics 1985;88:111-116. 21. Ngan P, Kess B, Wilson S. Pe rception of discomfort by patients undergoing orthodontic treatment. Am erican Journal of Orthodontics and Dentofacial Ort hopedics 1989;96:47-53. 22. Brown DF, Moerenhout RG. The pain experience and psychological adjustments to orthodontic treatment of preadolescents, adolescents and adults. American Journal of Orth odontics and Dentofacial Orthopedics 1991;100:349-356 23. Bergius M, Kiliardis S, Berggren U. Pain in orthodontics: a review and discussion of the literatur e. Journal of Orof acial Orthopedics 2000;61:125137. 37

PAGE 38

24. Ingersoll BD. Behavioral aspects in dentistry. Appleton Century Corfts, East Norwalt, CT. 1982. 25. Scheurer PA, Firestone AR, Burgin WB. Perception of pain as a result of orthodontic treatment with fixed appliances. European Journal of Orthodontics 1996;18:349-357. 26. Jones ML, Chan C. Pain in the early stages of orthodontic treatment. Journal of Clinical Or thodontics 1992;26:311-313. 27. Erdin AM, Diner B. Perception of pain during orthodont ic treatment with fixed appliances. European Jour nal of Orthodontics 2004;26:79-85. 28. Sandy IR, Harris M. Prostagl andin and tooth movement. European Journal of Ort hodontics 1984;6:175-182. 29. Malmberg AB, Yaksh TL. Hyperalgesia mediated by spinal glutamate or substance P receptor blockade by sp inal cyclooxygenase inhibition. Science 1992;257:1276-1279. 30. Bjorkman R, Hallm an KM, Hedner J, Hedner T, Henning M. Nonsteroidal antiinflammatory drug modulation of behavioral responses to intrathecal N-methyl-D-aspartate, but not to substance P and amino-methylisoxazole-propionic acid in the rat. Journal of Clinical Pharmacology 1996;36:20S-26S. 38

PAGE 39

BIOGRAPHICAL SKETCH Katherine B. Miller received her Bac helor of Science in zoology from Auburn University in Auburn, Alabama in 2001. She conti nued her education at the University of Alabama Birmingham College of Dentistry in Birmingham, Alabama and earned her Doctor of Dental Medicine in 2007. Upon completion of her dental training, she c ontinued her education at the University of Florida College of Dentistry in Gainesville, Flor ida earning a Master of Science with a certificate in orthodontics in 2010. 39