Citation
Effects of Preoperative Ibuprofen, Anxiety, and Gender on Post-Separator Placement Pain

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Title:
Effects of Preoperative Ibuprofen, Anxiety, and Gender on Post-Separator Placement Pain
Creator:
MINOR, VALERIE JEAN VONNOH ( Author, Primary )
Copyright Date:
2008

Subjects

Subjects / Keywords:
Analgesics ( jstor )
Anxiety ( jstor )
Dosage ( jstor )
Mastication ( jstor )
Medications ( jstor )
Orthodontics ( jstor )
Orthopedics ( jstor )
Pain ( jstor )
Placebos ( jstor )
Separators ( jstor )

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Source Institution:
University of Florida
Holding Location:
University of Florida
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Copyright Valerie Jean Vonnoh Minor. Permission granted to University of Florida to digitize and display this item for non-profit research and educational purposes. Any reuse of this item in excess of fair use or other copyright exemptions requires permission of the copyright holder.
Embargo Date:
7/24/2006
Resource Identifier:
73284456 ( OCLC )

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EFFECTS OF PREOPERATIVE IBUPROFEN, ANXIETY, AND GENDER ON POST-
SEPARATOR PLACEMENT PAIN















By

VALERIE JEAN VONNOH MINOR


A THESIS PRESENTED TO THE GRADUATE SCHOOL
OF THE UNIVERSITY OF FLORIDA IN PARTIAL FULFILLMENT
OF THE REQUIREMENTS FOR THE DEGREE OF
MASTER OF SCIENCE

UNIVERSITY OF FLORIDA


2006

































Copyright 2006

by

VALERIE JEAN VONNOH MINOR















ACKNOWLEDGMENTS

I thank my husband, Will, for his love and support over the past eight years. The

sacrifices that he has made mean more to me than words can express. I thank my son,

Harper, for bringing a new joy to my life and for helping me to keep things in

perspective. I would also like to thank my parents and other family members who have

believed in me and encouraged me to always strive for the best. Finally, I thank my

committee members and Dr. Calogero Dolce and Marie Taylor for all of their guidance

and assistance with this project.
















TABLE OF CONTENTS



A C K N O W L E D G M E N T S ......... ................................................................................... iii

LIST OF TABLES ........ .............. ........ ............ .......... .............. v

L IST O F F IG U R E S ...... ...... .......................... ........................ .. .. ...... ............ vi

ABSTRACT ........ .............. ............. ........ ..................... vii

CHAPTER

1 IN TR O D U C TIO N ......................................................................... .... .. ........

2 M E T H O D S ............................................................................. 4

3 R E SU L T S .............................................................................. 8

4 D ISCU SSION .............................................................................. 14

5 C O N C L U SIO N S ..................... .... .......................... .. .... ........ .... ......... ..2 1

L IST O F R E FE R E N C E S ............................................................................. .............. 22

B IO G R A PH IC A L SK E TCH ...................................................................... ..................26
















LIST OF TABLES

Table p

2 -1 : T reatm en t T im elin e .......................................................... ................ .......... .. .. ...5

3-1: B baseline (To) C characteristics ........................................ ................................. 8

3-2 : G ender C om prisons .................................................................. ......................... 9

3 -3 : P ain D iary ........................................................................................ 1 1
















LIST OF FIGURES


Figure page

3-1: Sum of mean VAS scores and standard errors for biting on the right and left sides
of the m south. ......................................................................... 12

3-2: Mean VAS scores and standard errors for fitting the back teeth together..................12

3-3: Sum of mean VAS scores and standard errors for all categories. ............................13















Abstract of Thesis Presented to the Graduate School
of the University of Florida in Partial Fulfillment of the
Requirements for the Degree of Master of Science

EFFECTS OF PREOPERATIVE IBUPROFEN, ANXIETY, AND GENDER ON POST-
SEPARATOR PLACEMENT PAIN

By

Valerie Jean Vonnoh Minor

May 2006

Chair: Timothy T. Wheeler
Major Department: Orthodontics

Many patients experience pain with orthodontics. However, there is no widely

accepted standard of care for controlling orthodontic pain. Previous studies have been

inconclusive as to the most effective way to manage orthodontic pain. The purpose of

this study was to assess the effectiveness of preemptive ibuprofen added to an ibuprofen

regimen administered after separator placement in reducing pain. The study also

assessed contributions of psychological factors and gender to pain. Subjects were

randomly assigned to Group A: 400 mg ibuprofen 1 hour before separator placement

(D1), 3 hours after placement (D2) and 7 hours after placement (D3); Group B: placebo

at D1, 400 mg ibuprofen at D2 and D3; or Group C: placebo at Dl, D2, and D3. Prior to

separator placement, subjects completed two psychological surveys, a Masticatory

Efficiency Test, and a Visual Analog Scale for expected pain and experienced pain

during the Masticatory Efficiency Test. After placement, subjects recorded the actual

pain experienced, kept a pain diary for 24 hours following separator placement, and









performed a 24-hour follow up Masticatory Efficiency Test. Significantly less pain

(p<0.05) was experienced at 6 hours, at bedtime, and at time of awakening on the second

day when ibuprofen was administered before and after separator placement. Preemptive

administration of ibuprofen is recommended to orthodontic patients before separator

placement.














CHAPTER 1
INTRODUCTION

A significant number of patients experience moderate to severe pain as a result of

initial orthodontic treatment.1-4 Orthodontic forces cause a disruption of the periodontal

tissues initiating a cascade of events involving the release of inflammatory mediators,

such as prostaglandins, into the local environment.5 Nonsteroidal anti-inflammatory

drugs (NSAIDs) act by inhibiting cyclooxygenase (COX) enzymes thereby blocking the

formation of prostaglandins and preventing both inflammation and the sensitization of

peripheral nociceptors.6 IfNSAIDs are given before a procedure, the body may absorb

and distribute the medication before tissue injury occurs. This could allow for a decrease

in the production of prostaglandins and thus a decrease in the inflammatory response.

Prior administration of NSAIDs may also exert an analgesic effect by blocking afferent

nerve impulses before they reach the central nervous system.8

Several authors have conducted studies evaluating pain following separator or

archwire placement. It has been found that pain is present within 4 hours and continues

until at least 24 hours dissipating by day 7.1,9,10 This is in agreement with other

studies,2'3 which have found the greatest need for analgesics to be within 3 days after

archwire placement. Bergius et al. found that 87% of participants reported pain on the

first evening, but the most intense pain was reported to occur the day after placement.

Females reported significantly higher pain during days 3-7 than males.

A limited number of similar studies have focused on orthodontic pain control.

Ngan et al.12 found ibuprofen and aspirin to provide more relief of orthodontic pain than









placebo when one dose was given immediately after separator or archwire placement.

They concluded that ibuprofen is the choice analgesic to control orthodontic pain since it

produced less pain than aspirin. Law et al.13 found that subjects who took preemptive

ibuprofen reported less pain at 2 hours than subjects who had placebo or ibuprofen after

separator placement. However, no significant differences were found between the post-

treatment group and the placebo group at any time during the seven days. Bernhardt et

al.14 found that subjects who received ibuprofen before separator placement or pre- and

post-treatment ibuprofen were in less pain at 2 hours and at bedtime than subjects who

received only post-treatment ibuprofen. No significant differences were found between

the pretreatment and combined therapy groups, but there was a trend toward decreasing

pain starting on day 2 for the combined therapy group.

Polat et al.15 evaluated the effects of one preemptive dose of ibuprofen (400mg),

naproxen sodium (550mg), or placebo given one hour before archwire placement.

Patients taking naproxen sodium had significantly less pain than the ibuprofen or placebo

groups at 2 hours, 6 hours, and nighttime. Although the pre-treatment ibuprofen group

showed a trend for decreased pain experienced at 2 hours and 6 hours, there were no

statistically significant differences between the placebo and ibuprofen groups. Another

study by Polat and Karaman16 compared orthodontic pain control achieved with a

preemptive and one post-treatment (6 hours after bonding) dose of 600 mg ibuprofen, 100

mg flurbiprofen, 500 mg acetaminophen, 550 mg naproxen sodium, 300 mg aspirin, or

placebo. The results showed that all of the analgesics decreased the pain compared to the

placebo group. However, the lowest pain levels were experienced by those taking

naproxen sodium, aspirin, and acetaminophen.









Currently, patients are told that separators may cause discomfort in the days

following placement. They are instructed to take over-the-counter pain medication as

needed for pain. Unfortunately, there is no widely accepted standard of care that is

followed for managing orthodontic pain. The intent of this study was to add to the body

of knowledge in determining an optimal treatment for controlling pain in orthodontics.

The specific purpose was to assess the effectiveness of preemptive ibuprofen added to an

ibuprofen regimen administered after separator placement in reducing pain. The study

also assessed contributions of psychological factors and gender to pain.














CHAPTER 2
METHODS

This was a double blind, parallel arm, prospective study that was approved by the

Institutional Review Board of University of Florida. In order to participate, patients had

to meet the following inclusion criteria: 1) at least 13 years of age and not older than 30,

2) females had to consent to a pregnancy test and could not be pregnant, 3) beginning

orthodontic treatment for the first time, 4) orthodontic treatment required the placement

of at least one separator in each of four quadrants, 5) no contraindications or adverse

reactions to ibuprofen or almonds, and 6) must give written informed consent for

participation in the study. Subjects were compensated for their participation with a $200

decrease in their orthodontic treatment fee. Fifty-one subjects were randomly assigned to

one of three groups stratifying for gender. (Table 2-1) Group A (16 subjects) received

400 mg ibuprofen 1 hour prior to separator placement (D1), 3 hours after separator

placement (D2), and 7 hours after separator placement (D3). Group B (17 subjects)

received placebo at Dl and 400 mg ibuprofen at D2 and D3. Group C (18 subjects), the

control group, received placebo at Dl, D2, and D3.

The investigational drug pharmacy at Shands Hospital dispensed the

ibuprofen/placebo so that the researcher would be blinded to the treatment group. Two

hundred mg caplets of ibuprofen were re-encapsulated and placebos were made to match.

Two capsules were taken at each dosing time.

A treatment timeline can be seen in Table 2-1. Prior to time of first dosing (Dl),

the subjects completed the following:










1) Expectation of pain: subjects were asked to rate their expectation of pain
consequent to separator placement using a 10 cm Visual Analog Scale (VAS). Anchors
of"no pain at all" (0 cm) and "worst pain imaginable" (10 cm) were used.17

2) Pre-existing affective state was assessed using the State and Trait Anxiety
Inventory (STAI)18 and the Positive Affect Negative Affect Schedule (PANAS)19.

3) Modified Mastication Performance Index20: subjects were asked to chew a
bagged almond five times on the right side of the mouth without swallowing. This was
repeated on the left side of the mouth. The protocol was modified from Al-Ali, Heath
and Wright, 1999.20 Subjects were asked to rate pain as a consequence of chewing the
almond on a VAS for both right and left sides.

4) If the patient was female and of child-bearing potential (i.e., post-menarche), a
pregnancy test was administered at this time. The results of the pregnancy test had to be
negative for the patient to continue as a participant in this study.

Table 2-1: Treatment Timelinea

To D1 Tx T1 D2 T2 D3 T3 T4 T5
Gp A: Gp A: Gp A:
Expected (n 16) 400mg 400mg
pain rating 400mg Ibuprofen Ibuprofen Masticatory
AN Ibuprofen Performance
Mastc Gp B: Gp B: Gp B: Index,
MPastcatory (n=17) Experienced Pain 400mg Pain 400mg Pain Pain xeee
Performance v Experienced
Index and Placebo Pain Rating Diary Ibuprofen Diary Ibuprofen Diary Diary Pain Rating
Experienced and Pain
Pain Rating Gp C: Gp C: Gp C: Diary
Pregnancy (n 18) Placebo Placebo
test for Placebo
females
-1.25hr -1 hr Separator +2 hr +3 hr +6 hr +7hr Bed Wake 24 hr
placement time up
aTo, prior to dosing; Tx, separator placement,; T1, 2 hours after separator placement; T2, 6 hours after separator placement; T3,
bedtime; T4, time of awakening; Ts, 24 hours after separator placement; D1, time of first dosing; D2, time of second dosing; D3, time of
third dosing

Separators were placed one hour after the first dosing and administration of the

above tests (TO). Ormco posterior separators (P/N 640-0080, Glendora, CA) were placed

unless the clinical situation warranted the use of metal separators. At least one separator

was placed in each quadrant. The method of placement, either over or under the contact,

was recorded for each separator placed. Pain upon 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.1,12-14 Pain scores were recorded in the pain diary at: 2 hours post-

separator placement (T1), 6 hours post-separator placement (T2), at bedtime (T3), at time

of awakening (T4) and at 24 hours post-separator placement (T5). Subjects provided the

specific times for bedtime and awakening in the pain diary. Subjects self-administered

the remaining two doses at 3 hours after separator placement (D2) and at 7 hours after

separator placement (D3). At 24 hours (T5), subjects self administered the masticatory

efficiency test with VAS. The completed pain diary and the chewed bagged almonds

were returned to the investigator by mail.

The chewed almond sample was removed from the bag and poured into a 10 mesh

sieve. The separated sample was then weighed. Part A was the portion of the original

almond weight that was remaining in the sieve and part B was the portion that passed

through the sieve. The bite efficiency was defined as % part B.20

Two investigators (CM and VM) with the same level of training did all data

collection and separator placement. Summary statistics and graphical methods were used

to examine the data. Two sample t-tests and analysis of variance were used for baseline

and 24 hour comparisons between treatment groups and between sexes. Relationships

between pain on placement and expected pain and pain on placement and psychological

variables were examined by calculating Pearson correlation coefficients. Linear mixed

models were used to examine the VAS pain ratings over time. An auto-regressive

correlation structure accounted for correlation within an individual, with pain measures

closer in time more highly correlated. The primary analysis outcome was the sum of pain

ratings (biting, right and left; chewing, right and left; fitting back teeth together; and

fitting front teeth together) at each time point, with secondary analyses done to examine









the separate components of biting, chewing, fitting back teeth together, and fitting front

teeth together. Initial models included variables representing the timepoints, treatment

group, and timepoint by treatment interaction. The interaction term allows for the pain

response pattern to vary over time, depending on treatment group. Contrasts were used to

assess treatment differences at each timepoint. The impact of adding additional

covariates to our primary model (sex, age, baseline characteristics) was also examined.

Akaike's information criterion was used to compare models. For all analyses, a p-value

of less than 0.05 was considered statistically significant.














CHAPTER 3
RESULTS

Baseline data (Table 3-1) showed no significant differences between groups for

gender, age, STAI, PANAS, expected pain, pain on separator placement, bite efficiency,

and pain during the bite efficiency test. Although the groups were stratified for gender,

group B ended up with only 41% females while group A had 63% females, and group C

had 72% females. However, this was not a statistically significant difference. The state

anxiety group averages were 32.6-33.3 (scale of 20-80) and the trait anxiety group

averages were 33.9-36.4. The positive affect group averages were 30.4-32.4 (scale of 10-

50) while the negative affect group averages were 13.4-15.1. The averages for expected

pain on placement, recorded with the VAS were 4.4-4.9 (on a scale of 0-10) while the

actual pain experienced was only 2.6-3.5. The average baseline bite efficiency ranged

from 19% to 29% while the average baseline pain during this bite test was 0.0-0.5.

Table 3-1: Baseline (To) Characteristics- Mean (standard deviation)b
Group A Group B Group C p-value
N 16 17 18
Gender (%female) 63 41 72 0.16
Age 17.6 (5.0) 14.9 (2.7) 16.4 (3.6) 0.15
State anxiety 33.3 (7.6) 33.3 (8.8) 32.6 (3.6) 0.95
Trait anxiety 36.4(7.2) 35.1 (7.4) 33.9(7.3) 0.62
Positive affect 30.8 (6.4) 32.4 (8.9) 30.4(8.3) 0.74
Negative affect 14.5 (4.4) 15.1 (3.5) 13.4 (3.3) 0.41
VAS expected 4.9(2.1) 4.7(1.8) 4.4(1.4) 0.72
VAS placement 3.1 (2.4) 3.5 (2.9) 2.6 (2.2) 0.59
Bite efficiency R 25 (26) 19 (23) 28 (24) 0.59
Bite efficiency L 29 (31) 26 (28) 28 (25) 0.96
VAS bite R 0.0(0.0) 0.2(0.3) 0.1(0.1) 0.16
VAS bite L 0.0(0.1) 0.5(1.5) 0.2(0.8) 0.43
bVAS expected, expectation of pain with separator placement; VAS placement, pain on placement; VAS bite R, pain during bite
efficiency test on right side; VAS bite L, pain during bite efficiency test on left side









There were no significant differences between groups A, B, or C for masticatory

efficiency index or pain with this test on either day 1 (Table 3-1) or on day 2 at 24 hours

(data not shown). There were significant decreases in bite efficiency and significant

increases in pain with this test from day 1 to day 2 (data not shown). However, there

were no differences between groups.

Males and females were compared for expected pain, pain on separator placement,

and the change in pain with the masticatory efficiency test from day 1 to day 2 (Table 3-

2). No statistically significant gender differences were found. However, there was a

trend for more pain on placement and a greater increase in pain with the 24 hour bite

efficiency test for females.

Table 3-2: Gender Comparisons- Mean (standard deviation)c
Males Females p-value
VAS expected 4.3 (1.8) 5.0(1.7) 0.17
VAS placement 2.4(2.4) 3.5(2.5) 0.10
Change in VAS bite R 5.9 (3.2) 7.2 (2.2) 0.09
Change in VAS bite L 5.7 (3.7) 7.1 (2.2) 0.14
'VAS expected, expectation of pain with separator placement; VAS placement, pain on placement; Change in VAS bite R, change in
pain during bite efficiency test on right from day 1 to day 2; Change in VAS bite L, change in pain during bite efficiency test on left
from day 1 to day 2.

Pearson correlation coefficients were calculated for pain on placement compared to

expected pain, STAI, and PANAS (Data not shown). No significant relationship was

found between the expected pain and actual pain experienced with separator placement.

Additionally, no significant correlations between pain on placement and PANAS or STAI

were found.

The results from the 24-hour pain diaries can be found in Table 3-3. Results for

biting, fitting back teeth together, and for the total pain experienced can be seen in

Figures 3-1,3-2, and 3-3. Figures for chewing and fitting front teeth together are not

shown but are similar to the others. At 6 hours, Group A (ibuprofen at all 3 dosing times)









experienced significantly less pain than both Groups B and C when biting and less than

Group C when chewing and fitting back teeth together. At this timepoint, Group A

reported less pain then Group B when fitting front teeth together. Group A was also

significantly different from the other two groups for the combined pain of chewing,

biting, fitting back teeth together, and fitting front teeth together. At bedtime, the pain

recorded by Group A was significantly less than that reported by the other two groups for

chewing and biting. Group A had less pain than Group C for fitting back teeth together

and less than Group B for fitting front teeth together at this timepoint. Group A also had

significantly less combined pain than the other groups at bedtime. By the morning of the

second day, Group A only differed from Group C when biting, and there was a rebound

effect by 24 hours with a trend for Group A to experience more pain than the other two

groups.

The following variables were added to the initial model of the sum of the pain

ratings: sex, age, state anxiety, trait anxiety, positive affect, negative affect, VAS for

expected pain, and VAS for pain on placement. Both main effect and added variable by

treatment group interactions were considered when appropriate. The only added variable

that was significant was VAS pain on placement. In the model containing VAS pain on

placement, each unit increase in this variable was associated with approximately a 2 unit

increase in the summary pain measure. Using this model to evaluate treatment

differences by timepoint, the 6 hour difference between groups A and B dropped to

marginal significance (p=0.0514), as might be expected since group B had a higher mean

VAS pain on placement score (3.5) than group A (3.1). Significance of the main effects









for this model are: timepoint, p<0.0001; treatment group, p=0.06; treatment group by

time point interaction, p=0.0065; and VAS pain on placement p=0.0017.

Table 3-3: Pain Diary- Mean VAS scores (standard error)d
Timepoint Group A Group B Group C Significance
Chewing 2 hrs 3.6(1.2) 5.9(1.4) 4.8(1.0)
(Sum ofR/L) 6 hrs 4.1 (1.3) 7.2 (1.3) 8.5 (1.3) A < C
Bedtime 3.0 (0.6) 7.3 (1.3) 9.9 (1.3) A < B, C
Awakening 7.3 (1.4) 9.2 (1.5) 10.3 (1.3)
24 hrs 11.6(2.1) 10.3 (1.7) 11.9 (1.1)
Biting 2 hrs 3.4(1.2) 5.6(1.2) 4.5(1.0)
(Sum ofR/L) 6 hrs 3.8 (1.3) 7.9 (1.4) 8.0 (1.2) A < B, C
Bedtime 2.8 (0.6) 7.4 (1.4) 10.0 (1.2) A < B, C
Awakening 6.5(1.4) 8.2(1.5) 10.2(1.1) A 24 hrs 11.8(2.0) 9.4(2.1) 11.7(1.2)
Fitting Back 2 hrs 1.2(0.4) 2.8(0.6) 1.9(0.5)
Teeth Together 6 hrs 2.0 (0.7) 2.9 (0.7) 3.2 (0.6)
Bedtime 1.5(0.4) 3.3 (0.8) 4.4(0.7) A Awakening 3.2 (0.8) 3.6 (0.8) 4.5 (0.6)
24 hrs 5.2 (1.0) 4.2 (1.0) 4.8 (0.8)
Fitting Front 2 hrs 0.4(0.1) 1.8(0.6) 0.4(0.2)
Teeth Together 6 hrs 0.3 (0.1) 2.4 (0.6) 1.6 (0.5) A Bedtime 0.8(0.3) 2.6(0.8) 1.7(0.5) A Awakening 2.0 (0.7) 2.6 (0.8) 2.5 (0.5)
24 hrs 3.3 (1.1) 2.8(1.1) 2.7(0.8)
Total Pain 2 hrs 8.6(2.7) 16.1 (3.8) 11.7(2.5)
6 hrs 10.3 (3.3) 20.3 (3.7) 21.3 (3.1) A < B, C
Bedtime 8.1(1.8) 20.7(4.1) 25.9(3.1) A < B, C
Awakening 19.1(3.7) 23.6(4.1) 27.5(3.2)
24 hrs 31.9(5.7) 26.8 (5.6) 31.1 (3.2)
d Significance based on p-values from mixed models








12




Biting


2 hrs 6 hrs bedtime awakening 24 hrs
Timepoint


Figure 3-1: Sum of mean VAS

sides of the mouth.


scores and standard errors for biting on the right and left
*p<0.05.


Fitting Back Teeth Together


2 hrs 6 hrs bedtime awakening 24 hrs
Timepoint


Figure 3-2: Mean VAS scores
*p<0.05.


and standard errors for fitting the back teeth together.


140


120


S100
0

80
- o


60

E
40



20


00


*Group A
SGroup B
SGroup C


*Group A
SGroup B
SGroup C









13




Total Pain

40


35


30


o 25

4 EGroupA
c 20 -Group B
EGroupC

E 15


10


5



2 hrs 6 hrs bedtime awakening 24 hrs
Timepoint


Figure 3-3: Sum of mean VAS scores and standard errors for all categories. *p<0.05.














CHAPTER 4
DISCUSSION

The results of this study indicate that less pain is experienced with orthodontic

separators if 400 mg ibuprofen is taken collectively at 1 hour before, 3 hours after, and 7

hours after placement. The group that received preemptive and post-treatment ibuprofen

(Group A) experienced significantly less pain at 6 hours and at bedtime on the night of

separator placement. Group A also reported less pain on the morning after separator

placement for biting only. However, for the other categories, the pain experienced by

group A increased back up to the same levels as the other two groups by the next

morning. There also seemed to be a rebound effect with a trend for group A to report

more pain at 24 hours than the other two groups. This rebound effect would indicate that

additional doses should be given after the 7-hour dose in order to maintain the benefits of

the medication.

Contrary to what would be expected, there was not a significant difference between

the pain experienced by the group that took ibuprofen only after separator placement (B)

and the placebo group (C) during the first 24 hours. Group B only received post-

treatment ibuprofen, and those subjects experienced similar pain levels as the placebo

group. This could suggest that once the nociceptive pathway has been initiated, it is

difficult to manage the pain with ibuprofen. One might also suppose that the decrease in

pain experienced by group A was mainly due to a preemptive anti-inflammatory effect

rather than just the analgesic effect of ibuprofen. However, the anti-inflammatory effects

of ibuprofen are often not seen for a few days to a week after administration while the









analgesic effects are more immediate. This is evidenced by the higher and more

prolonged doses that are recommended for arthritis conditions versus that recommended

for pain.21 Therefore, it is more probable that the benefits of preemptive dosing seen in

our study were due to the analgesic properties of ibuprofen rather than the anti-

inflammatory effects. Future studies with more prolonged dosing periods are needed to

address the anti-inflammatory effects of preemptive ibuprofen. Another possible

explanation for the lack of significant differences between groups B and C could be a

placebo effect for group C since subjects were told that they had an equal chance of being

assigned to any of the three groups. The fact that Group A experienced significantly less

pain than Group B but not less than Group C while fitting front teeth together at 6 hours

and at bedtime could also be a demonstration of the power of the placebo effect.

It was also found that the amount of pain reported upon placement of separators

was a predictor for the amount of pain that would be recorded in the 24 hour pain diary.

This could be interpreted two different ways. A method of placement which would cause

an increased pain experience during separator placement could produce a more severe

inflammatory response that would increase the amount of pain experienced during the

first 24 hours. Also, it could be that subjects who report more pain with placement are

going to report more pain in the diaries because of their innate pain threshold and

tolerance levels.

The results from our study were similar to those of some other studies, but there

were also some differences. Ngan et al.12 found that a single dose of 400 mg ibuprofen

taken immediately after separator placement provided more pain relief than placebo at 2

hours, 6 hours, 24 hours, 2 days, and 3 days. The dose in the Ngan et al. study was not









"preemptive", but it was immediately post-treatment. This differs from our study

because our Group A received a 1-hour preemptive dose while our Group B received

only post-treatment ibuprofen that was not taken until 3 hours and 7 hours after separator

placement. In our Group B, the inflammatory cascade was already established by the

time any medication was given. This could explain why the Ngan et al. study showed

significantly less pain with the early post-treatment ibuprofen group than with the

placebo group while ours did not. Law et al.13 also found significantly less pain at 2

hours for the group that received ibuprofen before separator placement, and similar to our

results, they found no significant differences between the placebo group and the group

that only received ibuprofen after separator placement. Bernhardt et al.14 found

significantly lower pain levels at 2 hours and at bedtime for the group that only received

ibuprofen before separator placement and the group that received both pre-and post-

treatment ibuprofen. Polat et al.15 did not find significant differences between their

placebo group and the group that received ibuprofen 1 hour prior to archwire placement,

but they did find a trend for less pain at 2 hours and 6 hours. Our study did not find a

significant difference between any of the groups for pain at 2 or 24 hours. However,

there was a similar trend for our Group A to experience less pain at 2 hours and there

were significant differences at 6 hours and at bedtime.

All of these mentioned studies had slightly different results; however that is to be

expected with the variations in study design and the multi-dimensional nature of pain.

All of the studies used the VAS method for recording pain. Both the Law et al.13 and

Bernhardt et al.14 studies had small sample sizes due to high incidences of subjects

resorting to rescue medication. Our study also had a small sample size, but we had no









requests for rescue medication. This was most likely due to the protocol followed.

Subjects and parents were told to call anytime, day or night, if the subject was

experiencing enough pain to need medication. At this time, the investigator could

instruct the subject or parent on what medication could be taken. The subjects in the Law

et al.13 and Bernhardt et al.14 studies averaged about 13 years old while those in our study

and Polat's15 study were closer to 16 years old. As previously mentioned, the Polat et

al.15 study involved pain after archwire placement rather than separator placement. Other

possible differences could have been in the types of separators that were used or

differences in the method of placement, whether over or under the contact of the tooth.

Subjects in the Ngan et al.12 study had separators placed on the mesial and distal of all

first molars while subjects in our study had at least one separator placed per quadrant.

Although not reported in the studies, there could also have been differences in the times

of day that the separators were placed. This could influence results as levels of pain

sensitivity may fluctuate throughout the day.

It is not fully understood why our study did not find significant differences at 2

hours while we did at 6 hours, at bedtime, and at time of awakening. Since the peak

plasma concentration of ibuprofen is 1-2 hours it would be expected that there would be

differences among the groups in pain levels at 2 hours after separator placement. There

was a trend for group A to report less pain at 2 hours, and it is possible that a statistically

significant difference could be found with a larger sample size. The lack of differences at

24 hours could be explained by the fact that the last dose of ibuprofen was taken 7 hours

after separator placement, and the effects had diminished. Another point to consider is

that all subjects were given the same dosage of medication without taking weight into









consideration. It is possible that subjects who weighed less could have experienced

increased analgesic effects because of the higher concentration of medicine that they

received in comparison to heavier subjects.

A commonly accepted principle is that females have a lower pain threshold and less

pain tolerance than men. Scheurer et al.22 found perception of pain to be greater in

females than males. McGrath and Craig 23 discovered that pain experiences are reported

equally by males and females prior to puberty, but once gender differences emerge,

females reported a higher incidence and intensity of pain. Walker and Carmody24 found

that females did not experience a significant analgesic response to ibuprofen while males

did. Explanations that have been suggested to account for gender differences include

biologic mechanisms such as genetics and hormonal differences and social and

psychological factors such as developmental, emotional, and cognitive.25 Several other

investigations into orthodontic pain have discovered no gender differences with regard to

prevalence and intensity of pain.1-3,9,26,27 The results of our study were in agreement with

others that have shown no significant gender differences for orthodontic pain. However,

our data did show a trend for more pain on separator placement and for a greater increase

in pain with the 24 hour masticatory efficiency test for females. It is interesting that

studies of other types of pain have found significant gender differences while most of the

orthodontic studies have not. This could be because many of the other studies are done

on adults while the orthodontic subjects are primarily adolescents. It could also be

postulated that females do not perceive as much pain with orthodontics as they would

with other pain producing events because of their desire for the esthetic benefits of

orthodontic treatment.









Pain is a subjective, multi-dimensional sensation. The experience of pain is

extremely variable having contributions from cultural background, previous experience,

motivation, gender, personality, and psychological factors.1-3,22 Firestone et al.28

concluded that orthodontic patients' expectation of pain is significantly correlated with

perceived pain during treatment. Fillingim et al. 29 found that negative affect correlated

with lower pain tolerance for both males and females, but it was associated with poorer

analgesic response only for males while positive affect was associated with lower pain

sensitivity among males only.

Subjects in our study completed two psychological surveys before the first dosing

time. The STAI18 provides a measure of situational anxiety and anxiety as part of

personality while the PANAS19 assesses mood state characterized along the separate

dimensions of positive and negative affect. Both of these instruments have demonstrated

reliability and validity, and are widely used in clinical and experimental research.

Surprisingly, the results from our study did not reveal any contributions from STAI or

PANAS for the amounts of pain that were reported with separator placement or in the

pain diaries. It was expected that subjects who expected more pain would experience

more pain with separator placement. It was also anticipated that subjects with higher

anxiety scores, lower positive affect scores, and higher negative affect scores may report

higher levels of pain. Perhaps a larger sample size would have produced significant

findings for psychological factors.

Studies30'31 have found prostaglandin application to increase tooth movement in a

nearly 2 to 1 ratio. NSAIDs can cause a decrease in tooth movement due to their action

in blocking prostaglandin production.32-34 On the basis of these findings, it has been









suggested that NSAIDs should not be taken during orthodontic treatment to avoid a

decrease in tooth movement and an increase in treatment time.32'33 However, other

mediators like leukotrienes, cytokines and growth factors may also contribute to bone

resorption.35 Saito et al.35 found that indomethacin slowed tooth movement but did not

stop it. Tyrovola et al.34 suggest avoiding only the long-term administration of NSAIDs.

Short-term use, as in the present study, will only temporarily reduce the levels of

prostaglandins.12

While the majority of orthodontic patients would not discontinue treatment because

of separator pain, it has been shown that pain does negatively impact compliance.9'36'37

Because compliance is such a critical factor for successful orthodontic treatment, it is

important to be able to control orthodontic pain. Continued research is necessary in order

to derive a standard of care for controlling orthodontic pain so that patients will be more

comfortable, compliance will be improved, and orthodontic outcomes will be enhanced.














CHAPTER 5
CONCLUSIONS

The following conclusions were drawn from this study.

1) Preemptive administration of ibuprofen can decrease the amount of pain experienced
at 6 hours, at bedtime, and on the morning after separator placement.

2) Despite the use of analgesics, there is a decrease in chewing efficiency and an increase
in pain on day 2 indicating a need for additional or higher doses or a need for a longer
preemptive dosing period.















LIST OF REFERENCES


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8. Woolf CJ. Generation of acute pain: central mechanisms. British Medical Bulletin
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9. Sergl HG, Klages U, Zentner A. Pain and discomfort during orthodontic
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10. Wilson S, Ngan P, Kess B. Time course of the discomfort in young patients
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11. Bergius M, Berggren U, Kiliaridis S. Experience of pain during an orthodontic
procedure. European Journal of Oral Sciences 2002; 110: 92-98.









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discomfort in patients undergoing orthodontic treatment. American Journal of
Orthodontics and Dentofacial Orthopedics 1994; 106: 88-95.

13. 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 Journal of Orthodontics and Dentofacial Orthopedics 2000;
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The effect of preemptive and/or postoperative ibuprofen therapy for orthodontic
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16. Polat O, Karaman AI. Pain control during fixed orthodontic appliance therapy.
Angle Orthodontist 2005; 75: 210-215.

17. Seymour RA, Simpson JM, Charlton JE, Phillips ME. An evaluation of length
and end-phrase of visual analogue scales in dental pain. Pain 1985; 21: 177-185.

18. Spielberger CD. State-Trait Anxiety Inventory: a comprehensive bibliography.
2nd ed. Palo Alto: Consulting Psychologists Press, Inc; 1989.

19. Watson D, Clark LA, Tellegen A. Development and validation of brief measures
of positive and negative affect: the PANAS scales. Journal of Personality and
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20. Al-Ali F, Heath MR, Wright PS. Simplified method of estimating masticatory
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24. Walker JS, Carmody JJ. Experimental pain in health human subjects: Gender
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1985; Aug: 111-116.

27. Erdinc AME, Dincer B. Perception of pain during orthodontic treatment with
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related side effects and their perception of pain as a result of orthodontic
treatment with fixed appliances. European Journal of Orthodontics 1999; 21:
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29. Fillingim RB, Hastie BA, Ness TJ, Glover TL, Campbell CM, Staud R. Sex-
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32. Kehoe MJ, Cohen SM, Zarrinnia K, Cowan A. The effect of acetaminophen,
ibuprofen, and misoprostol on prostaglandin E2 synthesis and the degree and rate
of orthodontic movement. Angle Orthodontist 1996; 5: 339-49.

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25


35. Saito M, Saito S, Ngan PW, Shanfeld J, Davidovitch Z. Interleukin 1 beta and
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37. Bartsch A, Witt E, Sahm G, Schneider S. Correlates of objective patient
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BIOGRAPHICAL SKETCH

Valerie Jean Vonnoh Minor was born in Jacksonville, Florida. She graduated from

North Carolina State University in 1997 with B.S. degrees in chemical engineering and

pulp and paper science and technology. Valerie attended the University of Florida for her

dental education and graduated in 2003 with a Doctor of Dental Medicine degree. She

then continued her education at the University of Florida, earning a Master of Science

with a certificate in the specialization of orthodontics in May 2006.




Full Text

PAGE 1

EFFECTS OF PREOPERATIVE IBUPROFE N, ANXIETY, AN D GENDER ON POSTSEPARATOR PLACEMENT PAIN By VALERIE JEAN VONNOH MINOR 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 2006

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Copyright 2006 by VALERIE JEAN VONNOH MINOR

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ACKNOWLEDGMENTS I thank my husband, Will, for his love and support over the past eight years. The sacrifices that he has made mean more to me than words can express. I thank my son, Harper, for bringing a new joy to my life and for helping me to keep things in perspective. I would also like to thank my parents and other family members who have believed in me and encouraged me to always strive for the best. Finally, I thank my committee members and Dr. Calogero Dolce and Marie Taylor for all of their guidance and assistance with this project. iii

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TABLE OF CONTENTS page ACKNOWLEDGMENTS .................................................................................................iii LIST OF TABLES ...............................................................................................................v LIST OF FIGURES ...........................................................................................................vi ABSTRACT ......................................................................................................................vii CHAPTER 1 INTRODUCTION........................................................................................................1 2 METHODS...................................................................................................................4 3 RESULTS.....................................................................................................................8 4 DISCUSSION.............................................................................................................14 5 CONCLUSIONS........................................................................................................21 LIST OF REFERENCES...................................................................................................22 BIOGRAPHICAL SKETCH.............................................................................................26 iv

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LIST OF TABLES Table page 2-1: Treatment Timeline......................................................................................................5 3-1: Baseline (T 0 ) Characteristics........................................................................................8 3-2: Gender Comparisons....................................................................................................9 3-3: Pain Diary...................................................................................................................11 v

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LIST OF FIGURES Figure page 3-1: Sum of mean VAS scores and standard errors for biting on the right and left sides of the mouth.............................................................................................................12 3-2: Mean VAS scores and standard errors for fitting the back teeth together..................12 3-3: Sum of mean VAS scores and standard errors for all categories...............................13 vi

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Abstract of Thesis Presented to the Graduate School of the University of Florida in Partial Fulfillment of the Requirements for the Degree of Master of Science EFFECTS OF PREOPERATIVE IBUPROFEN, ANXIETY, AND GENDER ON POST-SEPARATOR PLACEMENT PAIN By Valerie Jean Vonnoh Minor May 2006 Chair: Timothy T. Wheeler Major Department: Orthodontics Many patients experience pain with orthodontics. However, there is no widely accepted standard of care for controlling orthodontic pain. Previous studies have been inconclusive as to the most effective way to manage orthodontic pain. The purpose of this study was to assess the effectiveness of preemptive ibuprofen added to an ibuprofen regimen administered after separator placement in reducing pain. The study also assessed contributions of psychological factors and gender to pain. Subjects were randomly assigned to Group A: 400 mg ibuprofen 1 hour before separator placement (D1), 3 hours after placement (D2) and 7 hours after placement (D3); Group B: placebo at D1, 400 mg ibuprofen at D2 and D3; or Group C: placebo at D1, D2, and D3. Prior to separator placement, subjects completed two psychological surveys, a Masticatory Efficiency Test, and a Visual Analog Scale for expected pain and experienced pain during the Masticatory Efficiency Test. After placement, subjects recorded the actual pain experienced, kept a pain diary for 24 hours following separator placement, and vii

PAGE 8

performed a 24-hour follow up Masticatory Efficiency Test. Significantly less pain (p<0.05) was experienced at 6 hours, at bedtime, and at time of awakening on the second day when ibuprofen was administered before and after separator placement. Preemptive administration of ibuprofen is recommended to orthodontic patients before separator placement. viii

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CHAPTER 1 INTRODUCTION A significant number of patients experience moderate to severe pain as a result of initial orthodontic treatment. 1-4 Orthodontic forces cause a disruption of the periodontal tissues initiating a cascade of events involving the release of inflammatory mediators, such as prostaglandins, into the local environment. 5 Nonsteroidal anti-inflammatory drugs (NSAIDs) act by inhibiting cyclooxygenase (COX) enzymes thereby blocking the formation of prostaglandins and preventing both inflammation and the sensitization of peripheral nociceptors. 6 If NSAIDs are given before a procedure, the body may absorb and distribute the medication before tissue injury occurs. This could allow for a decrease in the production of prostaglandins and thus a decrease in the inflammatory response. 7 Prior administration of NSAIDs may also exert an analgesic effect by blocking afferent nerve impulses before they reach the central nervous system. 8 Several authors have conducted studies evaluating pain following separator or archwire placement. It has been found that pain is present within 4 hours and continues until at least 24 hours dissipating by day 7. 1,9,10 This is in agreement with other studies, 2,3 which have found the greatest need for analgesics to be within 3 days after archwire placement. Bergius et al. 11 found that 87% of participants reported pain on the first evening, but the most intense pain was reported to occur the day after placement. Females reported significantly higher pain during days 3-7 than males. A limited number of similar studies have focused on orthodontic pain control. Ngan et al. 12 found ibuprofen and aspirin to provide more relief of orthodontic pain than 1

PAGE 10

2 placebo when one dose was given immediately after separator or archwire placement. They concluded that ibuprofen is the choice analgesic to control orthodontic pain since it produced less pain than aspirin. Law et al. 13 found that subjects who took preemptive ibuprofen reported less pain at 2 hours than subjects who had placebo or ibuprofen after separator placement. However, no significant differences were found between the post-treatment group and the placebo group at any time during the seven days. Bernhardt et al. 14 found that subjects who received ibuprofen before separator placement or preand post-treatment ibuprofen were in less pain at 2 hours and at bedtime than subjects who received only post-treatment ibuprofen. No significant differences were found between the pretreatment and combined therapy groups, but there was a trend toward decreasing pain starting on day 2 for the combined therapy group. Polat et al. 15 evaluated the effects of one preemptive dose of ibuprofen (400mg), naproxen sodium (550mg), or placebo given one hour before archwire placement. Patients taking naproxen sodium had significantly less pain than the ibuprofen or placebo groups at 2 hours, 6 hours, and nighttime. Although the pre-treatment ibuprofen group showed a trend for decreased pain experienced at 2 hours and 6 hours, there were no statistically significant differences between the placebo and ibuprofen groups. Another study by Polat and Karaman 16 compared orthodontic pain control achieved with a preemptive and one post-treatment (6 hours after bonding) dose of 600 mg ibuprofen, 100 mg flurbiprofen, 500 mg acetaminophen, 550 mg naproxen sodium, 300 mg aspirin, or placebo. The results showed that all of the analgesics decreased the pain compared to the placebo group. However, the lowest pain levels were experienced by those taking naproxen sodium, aspirin, and acetaminophen.

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3 Currently, patients are told that separators may cause discomfort in the days following placement. They are instructed to take over-the-counter pain medication as needed for pain. Unfortunately, there is no widely accepted standard of care that is followed for managing orthodontic pain. The intent of this study was to add to the body of knowledge in determining an optimal treatment for controlling pain in orthodontics. The specific purpose was to assess the effectiveness of preemptive ibuprofen added to an ibuprofen regimen administered after separator placement in reducing pain. The study also assessed contributions of psychological factors and gender to pain.

PAGE 12

CHAPTER 2 METHODS This was a double blind, parallel arm, prospective study that was approved by the Institutional Review Board of University of Florida. In order to participate, patients had to meet the following inclusion criteria: 1) at least 13 years of age and not older than 30, 2) females had to consent to a pregnancy test and could not be pregnant, 3) beginning orthodontic treatment for the first time, 4) orthodontic treatment required the placement of at least one separator in each of four quadrants, 5) no contraindications or adverse reactions to ibuprofen or almonds, and 6) must give written informed consent for participation in the study. Subjects were compensated for their participation with a $200 decrease in their orthodontic treatment fee. Fifty-one subjects were randomly assigned to one of three groups stratifying for gender. (Table 2-1) Group A (16 subjects) received 400 mg ibuprofen 1 hour prior to separator placement (D1), 3 hours after separator placement (D2), and 7 hours after separator placement (D3). Group B (17 subjects) received placebo at D1 and 400 mg ibuprofen at D2 and D3. Group C (18 subjects), the control group, received placebo at D1, D2, and D3. The investigational drug pharmacy at Shands Hospital dispensed the ibuprofen/placebo so that the researcher would be blinded to the treatment group. Two hundred mg caplets of ibuprofen were re-encapsulated and placebos were made to match. Two capsules were taken at each dosing time. A treatment timeline can be seen in Table 2-1. Prior to time of first dosing (D1), the subjects completed the following: 4

PAGE 13

5 1) Expectation of pain: subjects were asked to rate their expectation of pain consequent to separator placement using a 10 cm Visual Analog Scale (VAS). Anchors of no pain at all (0 cm) and worst pain imaginable (10 cm) were used. 17 2) Pre-existing affective state was assessed using the State and Trait Anxiety Inventory (STAI) 18 and the Positive Affect Negative Affect Schedule (PANAS) 19 3) Modified Mastication Performance Index 20 : subjects were asked to chew a bagged almond five times on the right side of the mouth without swallowing. This was repeated on the left side of the mouth. The protocol was modified from Al-Ali, Heath and Wright, 1999. 20 Subjects were asked to rate pain as a consequence of chewing the almond on a VAS for both right and left sides. 4) If the patient was female and of child-bearing potential (i.e., post-menarche), a pregnancy test was administered at this time. The results of the pregnancy test had to be negative for the patient to continue as a participant in this study. Table 2-1: Treatment Timeline a a T 0 prior to dosing; Tx, separator placement,; T 1 2 hours after separator placement; T 2 6 hours after separator placement; T 3 bedtime; T 4 time of awakening; T 5 24 hours after separator placement; D 1 time of first dosing; D 2 time of second dosing; D 3 time of third dosing T 0 D 1 Tx T 1 D 2 T 2 D 3 T 3 T 4 T 5 Gp A: (n=16) 400mg Ibuprofen Gp A: 400mg Ibuprofen Gp A: 400mg Ibuprofen Gp B: (n=17) Placebo Gp B: 400mg Ibuprofen Gp B: 400mg Ibuprofen Expected pain rating STAI, PANAS Masticatory Performance Index and Experienced Pain Rating Pregnancy test for females Gp C: (n=18) Placebo Experienced Pain Rating Pain Diary Gp C: Placebo Pain Diary Gp C: Placebo Pain Diary Pain Diary Masticatory Performance Index Experienced Pain Rating and Pain Diary -1.25hr -1 hr Separator placement +2 hr +3 hr +6 hr +7hr Bed time Wake up 24 hr Separators were placed one hour after the first dosing and administration of the above tests (T0). Ormco posterior separators (P/N 640-0080, Glendora, CA) were placed unless the clinical situation warranted the use of metal separators. At least one separator was placed in each quadrant. The method of placement, either over or under the contact, was recorded for each separator placed. Pain upon 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

PAGE 14

6 used in other studies. 1,12-14 Pain scores were recorded in the pain diary at: 2 hours post-separator placement (T1), 6 hours post-separator placement (T2), at bedtime (T3), at time of awakening (T4) and at 24 hours post-separator placement (T5). Subjects provided the specific times for bedtime and awakening in the pain diary. Subjects self-administered the remaining two doses at 3 hours after separator placement (D2) and at 7 hours after separator placement (D3). At 24 hours (T5), subjects self administered the masticatory efficiency test with VAS. The completed pain diary and the chewed bagged almonds were returned to the investigator by mail. The chewed almond sample was removed from the bag and poured into a 10 mesh sieve. The separated sample was then weighed. Part A was the portion of the original almond weight that was remaining in the sieve and part B was the portion that passed through the sieve. The bite efficiency was defined as % part B. 20 Two investigators (CM and VM) with the same level of training did all data collection and separator placement. Summary statistics and graphical methods were used to examine the data. Two sample t-tests and analysis of variance were used for baseline and 24 hour comparisons between treatment groups and between sexes. Relationships between pain on placement and expected pain and pain on placement and psychological variables were examined by calculating Pearson correlation coefficients. Linear mixed models were used to examine the VAS pain ratings over time. An auto-regressive correlation structure accounted for correlation within an individual, with pain measures closer in time more highly correlated. The primary analysis outcome was the sum of pain ratings (biting, right and left; chewing, right and left; fitting back teeth together; and fitting front teeth together) at each time point, with secondary analyses done to examine

PAGE 15

7 the separate components of biting, chewing, fitting back teeth together, and fitting front teeth together. Initial models included variables representing the timepoints, treatment group, and timepoint by treatment interaction. The interaction term allows for the pain response pattern to vary over time, depending on treatment group. Contrasts were used to assess treatment differences at each timepoint. The impact of adding additional covariates to our primary model (sex, age, baseline characteristics) was also examined. Akaikes information criterion was used to compare models. For all analyses, a p-value of less than 0.05 was considered statistically significant.

PAGE 16

CHAPTER 3 RESULTS Baseline data (Table 3-1) showed no significant differences between groups for gender, age, STAI, PANAS, expected pain, pain on separator placement, bite efficiency, and pain during the bite efficiency test. Although the groups were stratified for gender, group B ended up with only 41% females while group A had 63% females, and group C had 72% females. However, this was not a statistically significant difference. The state anxiety group averages were 32.6-33.3 (scale of 20-80) and the trait anxiety group averages were 33.9-36.4. The positive affect group averages were 30.4-32.4 (scale of 10-50) while the negative affect group averages were 13.4-15.1. The averages for expected pain on placement, recorded with the VAS were 4.4-4.9 (on a scale of 0-10) while the actual pain experienced was only 2.6-3.5. The average baseline bite efficiency ranged from 19% to 29% while the average baseline pain during this bite test was 0.0-0.5. Table 3-1: Baseline (T 0 ) CharacteristicsMean (standard deviation) b Group A Group B Group C p-value N 16 17 18 Gender (%female) 63 41 72 0.16 Age 17.6 (5.0) 14.9 (2.7) 16.4 (3.6) 0.15 State anxiety 33.3 (7.6) 33.3 (8.8) 32.6 (3.6) 0.95 Trait anxiety 36.4 (7.2) 35.1 (7.4) 33.9 (7.3) 0.62 Positive affect 30.8 (6.4) 32.4 (8.9) 30.4 (8.3) 0.74 Negative affect 14.5 (4.4) 15.1 (3.5) 13.4 (3.3) 0.41 VAS expected 4.9 (2.1) 4.7 (1.8) 4.4 (1.4) 0.72 VAS placement 3.1 (2.4) 3.5 (2.9) 2.6 (2.2) 0.59 Bite efficiency R 25 (26) 19 (23) 28 (24) 0.59 Bite efficiency L 29 (31) 26 (28) 28 (25) 0.96 VAS bite R 0.0 (0.0) 0.2 (0.3) 0.1 (0.1) 0.16 VAS bite L 0.0 (0.1) 0.5 (1.5) 0.2 (0.8) 0.43 b VAS expected, expectation of pain with separator placement; VAS placement, pain on placement; VAS bite R, pain during bite efficiency test on right side; VAS bite L, pain during bite efficiency test on left side 8

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9 There were no significant differences between groups A, B, or C for masticatory efficiency index or pain with this test on either day 1 (Table 3-1) or on day 2 at 24 hours (data not shown). There were significant decreases in bite efficiency and significant increases in pain with this test from day 1 to day 2 (data not shown). However, there were no differences between groups. Males and females were compared for expected pain, pain on separator placement, and the change in pain with the masticatory efficiency test from day 1 to day 2 (Table 3-2). No statistically significant gender differences were found. However, there was a trend for more pain on placement and a greater increase in pain with the 24 hour bite efficiency test for females. Table 3-2: Gender ComparisonsMean (standard deviation) c Males Females p-value VAS expected 4.3 (1.8) 5.0 (1.7) 0.17 VAS placement 2.4 (2.4) 3.5 (2.5) 0.10 Change in VAS bite R 5.9 (3.2) 7.2 (2.2) 0.09 Change in VAS bite L 5.7 (3.7) 7.1 (2.2) 0.14 c VAS expected, expectation of pain with separator placement; VAS placement, pain on placement; Change in VAS bite R, change in pain during bite efficiency test on right from day 1 to day 2; Change in VAS bite L, change in pain during bite efficiency test on left from day 1 to day 2. Pearson correlation coefficients were calculated for pain on placement compared to expected pain, STAI, and PANAS (Data not shown). No significant relationship was found between the expected pain and actual pain experienced with separator placement. Additionally, no significant correlations between pain on placement and PANAS or STAI were found. The results from the 24-hour pain diaries can be found in Table 3-3. Results for biting, fitting back teeth together, and for the total pain experienced can be seen in Figures 3-1,3-2, and 3-3. Figures for chewing and fitting front teeth together are not shown but are similar to the others. At 6 hours, Group A (ibuprofen at all 3 dosing times)

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10 experienced significantly less pain than both Groups B and C when biting and less than Group C when chewing and fitting back teeth together. At this timepoint, Group A reported less pain then Group B when fitting front teeth together. Group A was also significantly different from the other two groups for the combined pain of chewing, biting, fitting back teeth together, and fitting front teeth together. At bedtime, the pain recorded by Group A was significantly less than that reported by the other two groups for chewing and biting. Group A had less pain than Group C for fitting back teeth together and less than Group B for fitting front teeth together at this timepoint. Group A also had significantly less combined pain than the other groups at bedtime. By the morning of the second day, Group A only differed from Group C when biting, and there was a rebound effect by 24 hours with a trend for Group A to experience more pain than the other two groups. The following variables were added to the initial model of the sum of the pain ratings: sex, age, state anxiety, trait anxiety, positive affect, negative affect, VAS for expected pain, and VAS for pain on placement. Both main effect and added variable by treatment group interactions were considered when appropriate. The only added variable that was significant was VAS pain on placement. In the model containing VAS pain on placement, each unit increase in this variable was associated with approximately a 2 unit increase in the summary pain measure. Using this model to evaluate treatment differences by timepoint, the 6 hour difference between groups A and B dropped to marginal significance (p=0.0514), as might be expected since group B had a higher mean VAS pain on placement score (3.5) than group A (3.1). Significance of the main effects

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11 for this model are: timepoint, p<0.0001; treatment group, p=0.06; treatment group by time point interaction, p=0.0065; and VAS pain on placement p=0.0017. Table 3-3: Pain DiaryMean VAS scores (standard error) d Timepoint Group A Group B Group C Significance Chewing 2 hrs 3.6 (1.2) 5.9 (1.4) 4.8 (1.0) (Sum of R/L) 6 hrs 4.1 (1.3) 7.2 (1.3) 8.5 (1.3) A < C Bedtime 3.0 (0.6) 7.3 (1.3) 9.9 (1.3) A < B, C Awakening 7.3 (1.4) 9.2 (1.5) 10.3 (1.3) 24 hrs 11.6 (2.1) 10.3 (1.7) 11.9 (1.1) Biting 2 hrs 3.4 (1.2) 5.6 (1.2) 4.5 (1.0) (Sum of R/L) 6 hrs 3.8 (1.3) 7.9 (1.4) 8.0 (1.2) A < B, C Bedtime 2.8 (0.6) 7.4 (1.4) 10.0 (1.2) A < B, C Awakening 6.5 (1.4) 8.2 (1.5) 10.2 (1.1) A
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12 Biting0.02.04.06.08.010.012.014.02 hrs6 hrsbedtimeawakening24 hrsTimepointSum of Mean R and L VAS Scores Group A Group B Group C** Figure 3-1: Sum of mean VAS scores and standard errors for biting on the right and left sides of the mouth. *p<0.05. Fitting Back Teeth Together0.01.02.03.04.05.06.07.02 hrs6 hrsbedtimeawakening24 hrsTimepointMean VAS Score Group A Group B Group C* Figure 3-2: Mean VAS scores and standard errors for fitting the back teeth together. *p<0.05.

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13 Total Pain05101520253035402 hrs6 hrsbedtimeawakening24 hrsTimepointSum of Mean VAS Scores Group A Group B Group C** Figure 3-3: Sum of mean VAS scores and standard errors for all categories. *p<0.05.

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CHAPTER 4 DISCUSSION The results of this study indicate that less pain is experienced with orthodontic separators if 400 mg ibuprofen is taken collectively at 1 hour before, 3 hours after, and 7 hours after placement. The group that received preemptive and post-treatment ibuprofen (Group A) experienced significantly less pain at 6 hours and at bedtime on the night of separator placement. Group A also reported less pain on the morning after separator placement for biting only. However, for the other categories, the pain experienced by group A increased back up to the same levels as the other two groups by the next morning. There also seemed to be a rebound effect with a trend for group A to report more pain at 24 hours than the other two groups. This rebound effect would indicate that additional doses should be given after the 7-hour dose in order to maintain the benefits of the medication. Contrary to what would be expected, there was not a significant difference between the pain experienced by the group that took ibuprofen only after separator placement (B) and the placebo group (C) during the first 24 hours. Group B only received post-treatment ibuprofen, and those subjects experienced similar pain levels as the placebo group. This could suggest that once the nociceptive pathway has been initiated, it is difficult to manage the pain with ibuprofen. One might also suppose that the decrease in pain experienced by group A was mainly due to a preemptive anti-inflammatory effect rather than just the analgesic effect of ibuprofen. However, the anti-inflammatory effects of ibuprofen are often not seen for a few days to a week after administration while the 14

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15 analgesic effects are more immediate. This is evidenced by the higher and more prolonged doses that are recommended for arthritis conditions versus that recommended for pain. 21 Therefore, it is more probable that the benefits of preemptive dosing seen in our study were due to the analgesic properties of ibuprofen rather than the anti-inflammatory effects. Future studies with more prolonged dosing periods are needed to address the anti-inflammatory effects of preemptive ibuprofen. Another possible explanation for the lack of significant differences between groups B and C could be a placebo effect for group C since subjects were told that they had an equal chance of being assigned to any of the three groups. The fact that Group A experienced significantly less pain than Group B but not less than Group C while fitting front teeth together at 6 hours and at bedtime could also be a demonstration of the power of the placebo effect. It was also found that the amount of pain reported upon placement of separators was a predictor for the amount of pain that would be recorded in the 24 hour pain diary. This could be interpreted two different ways. A method of placement which would cause an increased pain experience during separator placement could produce a more severe inflammatory response that would increase the amount of pain experienced during the first 24 hours. Also, it could be that subjects who report more pain with placement are going to report more pain in the diaries because of their innate pain threshold and tolerance levels. The results from our study were similar to those of some other studies, but there were also some differences. Ngan et al. 12 found that a single dose of 400 mg ibuprofen taken immediately after separator placement provided more pain relief than placebo at 2 hours, 6 hours, 24 hours, 2 days, and 3 days. The dose in the Ngan et al. study was not

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16 preemptive, but it was immediately post-treatment. This differs from our study because our Group A received a 1-hour preemptive dose while our Group B received only post-treatment ibuprofen that was not taken until 3 hours and 7 hours after separator placement. In our Group B, the inflammatory cascade was already established by the time any medication was given. This could explain why the Ngan et al. study showed significantly less pain with the early post-treatment ibuprofen group than with the placebo group while ours did not. Law et al. 13 also found significantly less pain at 2 hours for the group that received ibuprofen before separator placement, and similar to our results, they found no significant differences between the placebo group and the group that only received ibuprofen after separator placement. Bernhardt et al. 14 found significantly lower pain levels at 2 hours and at bedtime for the group that only received ibuprofen before separator placement and the group that received both pre-and post-treatment ibuprofen. Polat et al. 15 did not find significant differences between their placebo group and the group that received ibuprofen 1 hour prior to archwire placement, but they did find a trend for less pain at 2 hours and 6 hours. Our study did not find a significant difference between any of the groups for pain at 2 or 24 hours. However, there was a similar trend for our Group A to experience less pain at 2 hours and there were significant differences at 6 hours and at bedtime. All of these mentioned studies had slightly different results; however that is to be expected with the variations in study design and the multi-dimensional nature of pain. All of the studies used the VAS method for recording pain. Both the Law et al. 13 and Bernhardt et al. 14 studies had small sample sizes due to high incidences of subjects resorting to rescue medication. Our study also had a small sample size, but we had no

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17 requests for rescue medication. This was most likely due to the protocol followed. Subjects and parents were told to call anytime, day or night, if the subject was experiencing enough pain to need medication. At this time, the investigator could instruct the subject or parent on what medication could be taken. The subjects in the Law et al. 13 and Bernhardt et al. 14 studies averaged about 13 years old while those in our study and Polats 15 study were closer to 16 years old. As previously mentioned, the Polat et al. 15 study involved pain after archwire placement rather than separator placement. Other possible differences could have been in the types of separators that were used or differences in the method of placement, whether over or under the contact of the tooth. Subjects in the Ngan et al. 12 study had separators placed on the mesial and distal of all first molars while subjects in our study had at least one separator placed per quadrant. Although not reported in the studies, there could also have been differences in the times of day that the separators were placed. This could influence results as levels of pain sensitivity may fluctuate throughout the day. It is not fully understood why our study did not find significant differences at 2 hours while we did at 6 hours, at bedtime, and at time of awakening. Since the peak plasma concentration of ibuprofen is 1-2 hours it would be expected that there would be differences among the groups in pain levels at 2 hours after separator placement. There was a trend for group A to report less pain at 2 hours, and it is possible that a statistically significant difference could be found with a larger sample size. The lack of differences at 24 hours could be explained by the fact that the last dose of ibuprofen was taken 7 hours after separator placement, and the effects had diminished. Another point to consider is that all subjects were given the same dosage of medication without taking weight into

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18 consideration. It is possible that subjects who weighed less could have experienced increased analgesic effects because of the higher concentration of medicine that they received in comparison to heavier subjects. A commonly accepted principle is that females have a lower pain threshold and less pain tolerance than men. Scheurer et al. 22 found perception of pain to be greater in females than males. McGrath and Craig 23 discovered that pain experiences are reported equally by males and females prior to puberty, but once gender differences emerge, females reported a higher incidence and intensity of pain. Walker and Carmody 24 found that females did not experience a significant analgesic response to ibuprofen while males did. Explanations that have been suggested to account for gender differences include biologic mechanisms such as genetics and hormonal differences and social and psychological factors such as developmental, emotional, and cognitive. 25 Several other investigations into orthodontic pain have discovered no gender differences with regard to prevalence and intensity of pain. 1-3,9,26,27 The results of our study were in agreement with others that have shown no significant gender differences for orthodontic pain. However, our data did show a trend for more pain on separator placement and for a greater increase in pain with the 24 hour masticatory efficiency test for females. It is interesting that studies of other types of pain have found significant gender differences while most of the orthodontic studies have not. This could be because many of the other studies are done on adults while the orthodontic subjects are primarily adolescents. It could also be postulated that females do not perceive as much pain with orthodontics as they would with other pain producing events because of their desire for the esthetic benefits of orthodontic treatment.

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19 Pain is a subjective, multi-dimensional sensation. The experience of pain is extremely variable having contributions from cultural background, previous experience, motivation, gender, personality, and psychological factors. 1-3,22 Firestone et al. 28 concluded that orthodontic patients expectation of pain is significantly correlated with perceived pain during treatment. Fillingim et al. 29 found that negative affect correlated with lower pain tolerance for both males and females, but it was associated with poorer analgesic response only for males while positive affect was associated with lower pain sensitivity among males only. Subjects in our study completed two psychological surveys before the first dosing time. The STAI 18 provides a measure of situational anxiety and anxiety as part of personality while the PANAS 19 assesses mood state characterized along the separate dimensions of positive and negative affect. Both of these instruments have demonstrated reliability and validity, and are widely used in clinical and experimental research. Surprisingly, the results from our study did not reveal any contributions from STAI or PANAS for the amounts of pain that were reported with separator placement or in the pain diaries. It was expected that subjects who expected more pain would experience more pain with separator placement. It was also anticipated that subjects with higher anxiety scores, lower positive affect scores, and higher negative affect scores may report higher levels of pain. Perhaps a larger sample size would have produced significant findings for psychological factors. Studies 30,31 have found prostaglandin application to increase tooth movement in a nearly 2 to 1 ratio. NSAIDs can cause a decrease in tooth movement due to their action in blocking prostaglandin production. 32-34 On the basis of these findings, it has been

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20 suggested that NSAIDs should not be taken during orthodontic treatment to avoid a decrease in tooth movement and an increase in treatment time. 32,33 However, other mediators like leukotrienes, cytokines and growth factors may also contribute to bone resorption. 35 Saito et al. 35 found that indomethacin slowed tooth movement but did not stop it. Tyrovola et al. 34 suggest avoiding only the long-term administration of NSAIDs. Short-term use, as in the present study, will only temporarily reduce the levels of prostaglandins. 12 While the majority of orthodontic patients would not discontinue treatment because of separator pain, it has been shown that pain does negatively impact compliance. 9,36,37 Because compliance is such a critical factor for successful orthodontic treatment, it is important to be able to control orthodontic pain. Continued research is necessary in order to derive a standard of care for controlling orthodontic pain so that patients will be more comfortable, compliance will be improved, and orthodontic outcomes will be enhanced.

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CHAPTER 5 CONCLUSIONS The following conclusions were drawn from this study. 1) Preemptive administration of ibuprofen can decrease the amount of pain experienced at 6 hours, at bedtime, and on the morning after separator placement. 2) Despite the use of analgesics, there is a decrease in chewing efficiency and an increase in pain on day 2 indicating a need for additional or higher doses or a need for a longer preemptive dosing period. 21

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LIST OF REFERENCES 1. Ngan P, Kess B, Wilson S. Perception of discomfort by patients undergoing orthodontic treatment. American Journal of Orthodontics and Dentofacial Orthopedics 1989; 96: 47-53. 2. Jones ML. An investigation into the initial discomfort caused by placement of an archwire. European Journal of Orthodontics 1984; 6: 48-54. 3. Jones M, Chan C. The pain and discomfort experienced during orthodontic treatment: a randomized controlled clinical trial of two initial aligning archwires. American Journal of Orthodontics and Dentofacial Orthopedics 1992; 102: 373-381. 4. Jones ML, Chan C. Pain in the early stages of orthodontic treatment. Journal of Clinical Orthodontics 1992; May: 311-313. 5. Urquhart E. Analgesic agents and strategies in the dental pain model. Journal of Dentistry 1994; 22: 336-341. 6. Mehlisch DR. The efficacy of combination analgesic therapy in relieving dental pain. Journal of the American Dental Association 2002; 133: 861-871. 7. Jackson DL, Moore PA, Hargreaves KM. Preoperative non-steroidal anti-inflammatory medication for the prevention of postoperative dental pain. Journal of the American Dental Association 1989; 119: 641-647. 8. Woolf CJ. Generation of acute pain: central mechanisms. British Medical Bulletin 1991; 47: 523-533. 9. Sergl HG, Klages U, Zentner A. Pain and discomfort during orthodontic treatment: causative factors and effects on compliance. American Journal of Orthodontics and Dentofacial Orthopedics 1998; 114: 684-691 10. Wilson S, Ngan P, Kess B. Time course of the discomfort in young patients undergoing orthodontic treatment. Pediatric Dentistry 1989; 11(2): 107-110. 11. Bergius M, Berggren U, Kiliaridis S. Experience of pain during an orthodontic procedure. European Journal of Oral Sciences 2002; 110: 92-98. 22

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23 12. Ngan P, Wilson S, Shanfeld J, Amini H. The effect of ibuprofen on the level of discomfort in patients undergoing orthodontic treatment. American Journal of Orthodontics and Dentofacial Orthopedics 1994; 106: 88-95. 13. 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 Journal of Orthodontics and Dentofacial Orthopedics 2000; 118: 629-635. 14. Bernhardt MK, Southard KA, Batterson KD, Logan HL, Baker KA, Jakobsen JR. The effect of preemptive and/or postoperative ibuprofen therapy for orthodontic pain. American Journal of Orthodontics and Dentofacial Orthopedics 2001; 120: 20-27. 15. Polat O, Karaman AI, Durmus E. Effects of preoperative ibuprofen and naproxen sodium on orthodontic pain. Angle Orthodontist 2005; 75: 791-796. 16. Polat O, Karaman AI. Pain control during fixed orthodontic appliance therapy. Angle Orthodontist 2005; 75: 210-215. 17. Seymour RA, Simpson JM, Charlton JE, Phillips ME. An evaluation of length and end-phrase of visual analogue scales in dental pain. Pain 1985; 21: 177-185. 18. Spielberger CD. State-Trait Anxiety Inventory: a comprehensive bibliography. 2nd ed. Palo Alto: Consulting Psychologists Press, Inc; 1989. 19. Watson D, Clark LA, Tellegen A. Development and validation of brief measures of positive and negative affect: the PANAS scales. Journal of Personality and Social Psychology 1988; 54(6): 1063-1070. 20. Al-Ali F, Heath MR, Wright PS. Simplified method of estimating masticatory performance. Journal of Oral Rehabilitation 1999; 26: 678-683. 21. PDR health [database on the Internet]. Thomson Physicians Desk Reference. c2004 [accessed 2006 March 22]. Available from: http://www.pdrhealth.com/drug_info/rxdrugprofiles/drugs/mot1276. 22. Scheurer PA, Firestone AR, Burgin WB. Perception of pain as a result of orthodontic treatment with fixed appliances. European Journal of Orthodontics 1996; 18(4): 349-357. 23. McGrath PJ, Craig KD. Developmental and psychological factors in childrens pain. Pediatric Clinics of North America 1989; 36: 823-836.

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24 24. Walker JS, Carmody JJ. Experimental pain in health human subjects: Gender differences in nociception and in response to ibuprofen. Anesthesia and Analgesia 1998; 86: 1257-1262. 25. Fillingim RB. Sex, gender, and pain: Women and men really are different. Current Pain and Headache Reports 2000; 4: 24-30. 26. Jones ML, Richmond S. Initial tooth movement: force application and pain a relationship? American Journal of Orthodontics and Dentofacial Orthopedics 1985; Aug: 111-116. 27. Erdinc AME, Dincer B. Perception of pain during orthodontic treatment with fixed appliances. European Journal of Orthodontics 2004; 26: 79-85. 28. Firestone AR, Scheurer PA, Burgin WB. Patients anticipation of pain and pain-related side effects and their perception of pain as a result of orthodontic treatment with fixed appliances. European Journal of Orthodontics 1999; 21: 387-396. 29. Fillingim RB, Hastie BA, Ness TJ, Glover TL, Campbell CM, Staud R. Sex-related psychological predictors of baseline pain perception and analgesic responses to pentazocine. Biological Psychology 2005; 69: 97-112. 30. Lee W. Experimental study of the effect of prostaglandin administration on tooth movement with particular emphasis on the relationship to the method of PGE1 administration. American Journal of Orthodontics and Dentofacial Orthopedics 1990; Sep: 231-241. 31. Yamasaki K, Shibata Y, Imai S, Tani Y, Shibaski Y, Fukuhara T. Clinical application of prostaglandin E1 (PGE1) upon orthodontic tooth movement. American Journal of Orthodontics and Dentofacial Orthopedics 1984; Jun: 508-518. 32. Kehoe MJ, Cohen SM, Zarrinnia K, Cowan A. The effect of acetaminophen, ibuprofen, and misoprostol on prostaglandin E 2 synthesis and the degree and rate of orthodontic movement. Angle Orthodontist 1996; 5: 339-49. 33. Walker JB, Buring SM. NSAID impairment of orthodontic tooth movement. The Annals of Pharmacotherapy 2001; 35: 113-115. 34. Tyrovola JB, Spyropoulos MN. Effects of drugs and systemic factors on orthodontic treatment. Quintessence International 2001; 32: 365-371.

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25 35. Saito M, Saito S, Ngan PW, Shanfeld J, Davidovitch Z. Interleukin 1 beta and prostaglandin E are involved in the response of periodontal cells to mechanical stress invivo and invitro. American Journal of Orthodontics and Dentofacial Orthopedics 1991; 99: 226-240. 36. Egolf RJ, BeGole Ea, Upshaw HS. Factors associated with orthodontic patient compliance with intraoral elastic and headgear wear. American Journal of Orthodontics and Dentofacial Orthopedics 1990; 97: 336-48. 37. Bartsch A, Witt E, Sahm G, Schneider S. Correlates of objective patient compliance with removable appliance wear. American Journal of Orthodontics and Dentofacial Orthopedics 1993; 104: 378-86.

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BIOGRAPHICAL SKETCH Valerie Jean Vonnoh Minor was born in Jacksonville, Florida. She graduated from North Carolina State University in 1997 with B.S. degrees in chemical engineering and pulp and paper science and technology. Valerie attended the University of Florida for her dental education and graduated in 2003 with a Doctor of Dental Medicine degree. She then continued her education at the University of Florida, earning a Master of Science with a certificate in the specialization of orthodontics in May 2006. 26