Postoperative Pain Management with a Steroid in Teeth Diagnosed

with Pulpal Necrosis

A Thesis

Presented in Partial Fulfillment of the Requirements for

the Degree of Master of Science in the

Graduate School of The Ohio State University

By

Michael D. Fuller D.D.S.

Graduate Program in Dentistry

The Ohio State University

2017

Master’s Examination Committee:

Melissa Drum, D.D.S., M.S., Advisor

Al Reader, D.D.S., M.S.

John Nusstein, D.D.S., M.S.

Sara Fowler, D.M.D., M.S.

F. Michael Beck, D.D.S., M.A.

Copyright by

Michael D. Fuller, D.D.S.

2017

Abstract

Introduction: Previous studies in clinical conditions without infection have

shown positive effects of steroids in controlling postoperative pain. The purpose of this

study is to evaluate whether a steroid will reduce pain in a symptomatic clinical condition

of pulpal necrosis.

Methods: Eighty-three patients presenting for emergency debridement of a

symptomatic tooth diagnosed with pulpal necrosis participated. All patients received

local anesthesia and endodontic debridement, and were randomly divided into two

groups. In a double-blind manner, the study groups received either a 96 mg dose (4

capsules) of methylprednisolone or an identical placebo (4 capsules) immediately

following debridement. They were instructed to take 48 mg (2 capsules) of the same

medication, or placebo (2 capsules), upon waking for five consecutive days. All patients

received 600 mg ibuprofen tablets to take as needed, and also a prescription of Tylenol #3

to take only if the ibuprofen did not control their pain. Patients were given an eight-day

journal to record their pain levels. Success was defined as no or mild postoperative pain

and no narcotic use. Results for success were analyzed using a chi-square test of fixed effects.

ii Results: The success rate of the steroid group was 49% and 48% for the placebo group with no significant difference between the groups.

Conclusions: For symptomatic patients diagnosed with pulpal necrosis, a high dose of methylprednisolone did not significantly increase success, defined as no or mild postoperative pain and no narcotic use, when compared to a placebo.

iii DEDICATION

To Tiffany - thank you for going on this journey with me! You never hesitated to let me follow my dreams, and I can’t thank you enough for your unselfish support.

To Graham, Lucas, and Scarlett - you provide me with never ending inspiration.

To my parents, your guidance and support is always with me.

iv

ACKNOWLEDGMENTS

Drs. Drum, Reader, Nusstein, Fowler, and Beck - Your motivation and guidance has been

invaluable. Your work ethic is admirable, and you bring the best out of those around

you. Your dedication to endodontics and this program has left us all with a fantastic

experience that will never be forgotten.

To my fellow residents: #, Chief, and Mama Liv - I wouldn’t want to experience this

program with any other group. It has truly been fun every day to come and have

conversations about late night escapades, hunting, bows (the hair type), and Costco.

Thank you for making this experience great. Cheers!

v

VITA

April 3, 1984 ...... Born: Medina, OH

May 2006 ...... Bachelor of Science, Business Management Miami University Oxford, OH

May 2010 ...... Doctor of Dental Surgery The Ohio State University College of Dentistry Columbus, OH

June 2011 ...... General Practice Residency Denver VAMC Denver, CO

August 2017 ...... Specialization in Endodontics Post-Doctoral Certificate The Ohio State University College of Dentistry Columbus, OH

FIELD OF STUDY

Major Field: Dentistry

Specialization: Endodontics

vi

TABLE OF CONTENTS

Page

Abstract ...... ii

Dedication ...... iv

Acknowledgments...... v

Vita ...... vi

Table of Contents ...... vii

List of Tables ...... ix

List of Figures ...... x

Chapters:

1. Introduction ...... 1

2. Materials and Methods ...... 3

3. Results ...... 11

4. Discussion ...... 15

5. Summary and Conclusions ...... 65

6. References ...... 67

Appendices

A. Tables ...... 77

B. Figures...... 90

vii

C. Initial Pain Visual Analog Scale ...... 95

D. Health History ...... 97

E. Consent Form ...... 100

F. Privacy Form ...... 108

G. Injection Pain Visual Analog Scale ...... 112

H. Treatment Pain Visual Analog Scale ...... 114

I. Anesthesia Grade ...... 116

J. Patient Pain Journal...... 118

viii LIST OF TABLES

Table Page

1 Evaluation of Initial Pain, Age, Weight, and Antibiotic Use ...... 78

2 Breakdown of Gender between Groups ...... 79

3 Preoperative Analgesic Use ...... 80

4 Injection Pain ...... 81

5 Treatment Pain ...... 82

6 Percentages and Discomfort Ratings of Steroid and Placebo Groups ...... 83

7 Swelling Status...... 84

8 Mean Number of Analgesic Tablets Utilized by Day ...... 85

9 Mean Number of Ibuprofen Tablets Utilized by Day ...... 86

10 Escape Drug Use by Day ...... 87

11 Success by Day ...... 88

12 Type III Tests of Fixed Effects of Success ...... 89

ix

LIST OF FIGURES

Figure Page

1 Postoperative Pain by Group and Day ...... 91

2 Total Analgesic Use ...... 92

3 Ibuprofen Use by Group and Day ...... 93

4 Success by Day ...... 94

x

Chapter 1: Introduction

Endodontic debridement is the treatment of choice for patients diagnosed with

pulpal necrosis (1). Unfortunately, patients can still have pain after endodontic

debridement (1,2). Possibly, the administration of a steroid would help decrease this

postoperative pain.

In previous investigations, an intracanal steroid was effective in reducing

postoperative pain in vital teeth but not in teeth with pulpal necrosis (3,4,5). An

intraligamentary injection of Depo-Medrol significantly reduced the frequency and

intensity of postoperative pain following routine endodontic treatment of vital teeth (6).

Pulpal pain from an untreated irreversible pulpitis can be temporarily reduced using an

intraosseous injection of Depo-Medrol (7,8). However, there are substantial differences

in the quantity and quality of periapical inflammation in the patient with symptomatic

irreversible pulpitis and the symptomatic patient with pulpal necrosis and a periapical

area.

In preliminary studies, other investigators (9,10) have evaluated methylprednisolone on postoperative pain in symptomatic patients presenting with pulpal necrosis and periapical radioluencies. Bramy et al. determined the effects of a 40 mg intraosseous dose of slow-releasing methylprednisolone (Depo-Medrol)(9). They found a

1

reduction in pain and analgesic use in the Depo-Medrol group but the results were not

significant. The authors felt that the insoluble acetate form of the Depo-Medrol may

dissolve too slowly, not providing enough of the drug to be effective (9). Claffey et al.

evaluated the effects of an oral dose of 48 mg of methylprednisolone, taken each day for

three days, on postoperative pain in symptomatic teeth with a pulpal diagnosis of necrosis

(10). They found that the methylprednisolone reduced pain and the use of pain

medication for the first three postoperative days when compared to a placebo. However,

on the day of endodontic treatment, and on days 4 through 7, patients had moderate or

severe pain, or took a large number of analgesic drugs. The authors theorized that the

initial dose of methylprednisolone was too low and had worn off later in the week

resulting in a rebound of inflammation and pain (10).

The rationale for this study was to increase the amount of oral methylprednisolone on the day of treatment from 48 mg to 96 mg and extend the 48 mg dose past three days

(48 mg to be given for five postoperative days), which may decrease moderate or severe postoperative pain to clinically manageable levels. This increased dosing is based on multiple medical studies conducted with much higher doses with very little adverse effects (11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21).

The purpose of this study was to evaluate postoperative pain using an oral dose regimen of methylprednisolone in symptomatic patients diagnosed with pulpal necrosis.

2

Chapter 2: Materials and Methods

Ninety-eight patients were enrolled in the study. Eighty-three completed the

study in its entirety. Eight patients were excluded due to vital tissue encountered during

treatment, five for not returning their pain journals, one patient disclosed she had a previous peptic ulcer after instrumentation which excluded her taking the study medication, and 1 patient had a tooth extracted during the postoperative pain survey

period. All patients presented to the endodontic division of The Ohio State University

College of Dentistry experiencing moderate to severe pain as recorded on a 170 mm

Heft-Parker VAS (22)(Appendix C). Patients were in good health (ASA I or ASA II) as

determined by oral and written questioning (Appendix D).

Inclusion criteria were: age 18-65 years of age, English speaking, and healthy

(ASA I or II). Exclusion criteria included: anyone younger than age 18, anyone older

than age 65, non-English speaking, any contraindication to corticosteroids (peptic ulcers,

Crohns disease, Colitis, GI bleeds, GERD, active herpetic or fungal infections, and severe

osteoporosis, diabetes mellitus (Type I or II), or a compromised immune status), females

that were pregnant or nursing, and any contraindications to non-steroidal anti-

inflammatory pain medication. If a female was unsure of their pregnancy status, a

pregnancy test was offered (Osom®, Genzyme Diagnostics Corp, San Diego, CA).

3

Approval was granted through The Ohio State University Human Subjects Review

Committee on February 4th 2016. (2015H0428). Written consent and a HIPAA form was completed by each subject prior to enrollment in the study (Appendix F).

Each patient had a symptomatic tooth with a pulpal diagnosis of necrosis (AAE diagnosis of Necrotic/Symptomatic Apical Periodontitis or Necrotic/Acute apical abscess). A periapical radiolucency was visible on the preoperative radiograph. Pulp testing was conducted using Endo-Ice® refrigerant (1,1,1,2 tetrafluoroethane, The

Hygenic® Corporation, Akron, OH) and all teeth treated in the study had a negative response. There were no patients with active sinus tracts and no one that had more than mild intraoral swelling. Patients rated their current pain on a Heft-Parker visual analogue scale (VAS). This 170 mm scale was divided into four categories according to pain level: no pain was 0 mm; mild pain was greater than 0 mm and less than or equal to 54 mm

(faint, weak, mild); moderate pain was greater than 54 mm and less than 114 mm; and severe pain was equal to or greater than 114 mm (strong, intense, maximum possible).

Each patient included in the study rated their pain greater than 84 mm on the VAS (the visual marker for moderate pain)(Appendix C). The subjects were questioned about pain medication use in the previous eight hours and antibiotic use. The tooth number, age, gender, and subject weight were also recorded.

Prior to enrollment, the study groups were assigned 6-digit random numbers by the lead researcher (M.D.), using a random number generator from www.random.org.

The number assignment determined which drug regimen was administered postoperatively to the patient. Only the random numbers were recorded on the sheet in 4

order to maintain blinding of the experiment to both the operator (M.F.) and the patient.

The blinding of the methylprednisolone and placebo were done as follows. A registered

pharmacist compounded identical-appearing capsules of the methylprednisolone and placebo. Each capsule contained 24 mg of methylprednisolone or placebo. Fourteen capsules of the appropriate drug were placed in medication containers with the 6-digit

random numbers printed on the label. Therefore, the medication was blind to both the patient and the operator. The pharmacist prepared the master code sheet and assigned the random numbers to the bottles. A copy of the master list of 6-digit random numbers was supplied by the compounding pharmacist solely to the lead researcher (M.D.), and was not made available to anyone else during the data collection period.

Central Ohio Compounding Pharmacy (Columbus, OH) compounded all steroid and placebo preparations. Methylprednisolone (Professional Compounding Centers of

America, Houston, TX), activated charcoal (Humco, Texarkana, TX), and lactose

(Professional Compounding Centers of America, Houston, TX), all in bulk powder form, were purchased by the pharmacy. Methylprednisolone, activated charcoal and lactose were mixed by geometric dilution. Geometric dilution is a process of mixing medications together to assure equal dispersion of a mixture. The three compounds to be mixed were divided into an equal number of parts, and then mixed together at a 1:1:1 ratio, a 2:2:2 ratio, a 4:4:4 ratio and so on, until all compounds were mixed evenly. After mixing, the powder was encapsulated in #3 blue/green capsules (Shionogi Co., Indianapolis, IN) using a Jaansun Capsule Machine (Professional Compounding Centers of America,

Houston, TX). The Jaansun Capsule Machine is a mechanical device that allows a

5

pharmacist to fill 100 capsules at one time. This procedure was carried out to fill each of

630 #3 blue/green capsules. The pharmacy used lactose sugar in bulk powder form for

the placebo. Twenty-seven grams of lactose powder was measured and used to fill #3

blue/green capsules in the same manner as the steroid capsules, with the exception of the

methylprednisolone. A total of 630 placebo capsules were created. The 90 amber vials

were labeled with a 6-digit random number taken from the random number sheet already

described. Fourteen 24 mg capsules of methylprednisolone were placed in all vials with

6-digit codes that were assigned to group 1 (methylprednisolone). Fourteen 24 mg

capsules of lactose were placed in all vials with 6-digit codes that were assigned to group

0 (placebo).

Each patient was anesthetized using 2 cartridges of 1.8 ml of 2% lidocaine with

1:100,000 epinephrine (Xylocaine, AstraZeneca LP, Dentsply, York, PA) administered by inferior alveolar nerve block (IANB) or maxillary infiltration. Prior to needle insertion each patient was given topical anesthetic gel (20% benzocaine, Patterson Dental Supply,

Inc., St. Paul, MN) passively placed at the injection site for 60 seconds using a cotton tip

applicator. Following the first cartridge, patients were given a 170 mm VAS (Appendix

G), divided as described earlier, and recorded injection pain levels according to insertion

of the needle, placement of the needle, and deposition of the anesthetic. Insertion of the

needle corresponded to the penetration of the oral mucosa. Placement of the needle

corresponded to moving the needle to the desired location without giving any local

anesthesia. Deposition corresponded to the entire 60 seconds time of lidocaine

administration. During the injection, the patient was told when the needle was inserted,

6

when the needle was placed at the site of deposition, and when the solution was being

deposited. During each phase of the injection, the patient was told to remember their

pain levels. Immediately following solution deposition the patient was given the three

170 mm VAS’s to rate their pain levels (Appendix G). After the patient completed the

three 170 mm VAS’s, the second 1.8 ml of 2% lidocaine with 1:100,000 epinephrine

cartridge was administered. The second injection was not rated due to anesthesia already

having an effect after the first injection. If additional anesthetic was needed for a

mandibular tooth following profound lip numbness, a 1.7 ml buccal infiltration of 4%

septocaine with 1:100,000 epinephrine (Septocaine, Septodont, Dentsply, York, PA) was

administered (23). In one patient, profound lip numbness was not achieved, and a third

IANB was administered with 2% lidocaine 1:100,000 epinephrine. If additional anesthetic was needed for a maxillary tooth, a local infiltration injection using 1.8 ml of

2% lidocaine with 1:100,000 epinephrine was administered (23). Five patients who were undergoing debridement of a maxillary tooth needed additional anesthetic, and five patients who were undergoing debridement of a mandibular tooth needed additional anesthetic.

Following soft tissue anesthesia, a rubber dam was placed using a clamp and endodontic debridement was initiated. The patient recorded their pain levels on a 170 mm VAS at three points during the debridement: when the dentin was accessed, when the pulp chamber was accessed, and while the canals were being instrumented (Appendix

H). If the patient was experiencing discomfort, they were given additional local

7

anesthetic by IANB or local infiltration, and this was recorded. If vital pulp tissue was

observed in any canals during the debridement, the patient was excluded from the study.

Endodontic debridement was accomplished using a dental microscope to locate canals and identify pulp chamber anatomy. Once canals were located, files were placed and a digital radiograph was taken to establish working length 0.5 mm-1 mm from the radiographic apex. An apex locator (Root ZX II, J. Morita USA, Irvine, CA) was also utilized to confirm working length. Once working length was establish, a glide path was created using a #15 K-type hand file. Following initial shaping, Vortex rotary nickel- titanium endodontic files were used (Vortex, DENTSPLY International, Inc., Johnson

City, TN). The minimum final file size was 30 with a .04 taper. Throughout the treatment, 3% NaOCl (Clorox, Clorox Company, Oakland, CA) was used as irrigation.

As a final irrigation, the PiezoFlow ( DENTSPLY Tulsa Dental Specialties, York PA) irrigation needle was used with a ultrasonic handpiece. This allowed the use of continuous active ultrasonic irrigation using 3% NaOCl. Each canal was irrigated for 1 minute using the PiezoFlow. The canals were then dried with sterile paper points and calcium hydroxide (Multi-Cal, Pulpdent Corp, Watertown, MA) was placed in each canal using a capillary tip (0.014” Diameter Capillary Tip, Ultradent Products Inc.,

South Jordan, UT). The Ca(OH)2 was then worked into the canals with K-type hand files.

A cotton pellet was placed and the tooth was temporized with Gray Cavit G (3M ESPE,

Seefeld, Germany). Lastly, the rubber dam was removed. After the rubber dam was

removed, an overall anesthesia grade was completed by the operator (M.F.) and recorded

as Grade A (profoundly numb) Grade B (numb, some discomfort) Grade C (not numb,

8

felt discomfort, able to complete treatment), or Grade D (not numb, felt discomfort, had to re-inject) (Appendix I). Also, any drainage from the canals during debridement was recorded.

Following endodontic debridement, four capsules (96mg) of methylprednisolone

or placebo were given immediately postoperatively and taken by the patient in the

presence of the investigator. The patients were instructed to take two capsules (48 mg) of

methylprednisolone or placebo upon waking for the next five days postoperatively. Each

patient was also given sixteen tablets of 600 mg ibuprofen (Amneal Pharmaceuticals

Bridgewater, NJ) tablets in pill bottles. Patients were instructed to taken one ibuprofen

tablet as needed for pain every six hours. The ibuprofen was taken as a first line of

defense against pain. Patients were also given a prescription for sixteen tablets of

Tylenol #3 (acetaminophen 325 mg with 30 mg codeine). An assigned cell phone

number was placed at the top of the prescription and the pharmacist was instructed to call

prior to the prescription being filled. The patients were instructed to take one to two

tablets every six hours as needed for pain only if the ibuprofen was not managing the

pain. On each medication bottle the emergency on-call cell phone was given, so the

patient could contact the investigator if necessary. Following the initial debridement

appointment, the patients were given $20.00.

Each patient was given an 8-day journal to record pain levels on a Heft-Parker

VAS, type and amount of pain medication taken, whether the pain and/or swelling was

better, worse, or stayed the same, and subjective assessment of swelling (Appendix J).

The journal began at Day 0 (treatment day) and continued for 7 days postoperatively. If 9

the patient had any questions regarding completion of the diary, they were instructed to

call the on-call cell phone listed on the medication bottles. Following completion of day

7, patient’s returned the journal to the endodontic department along with any remaining

medication. The investigator was available to see the patients if they had any questions

or concerns. The number of pills remaining in the medication bottles was verified with

the journal count. Upon completion and return of the journal, patients were given $80.00.

The results starting at day 1 were analyzed. At the time the patients filled out the

journal on day 0 (night of treatment), the steroid medication may not have taken effect,

therefore that data was collected, but not analyzed. All VAS recordings were measured

using the same ruler by the same investigator. Age and presenting pain were assessed

preoperatively using the randomization test. The chi-square test (or the Fisher exact test if expected frequencies were <5) was used to evaluate preoperative group differences in gender, antibiotic use, narcotic use, NSAID use and tooth location. Postoperative pain ratings and drug use were evaluated using multiple randomization tests with p-values adjusted for multiple comparisons using the step-down Bonferroni method of Holm.

Success was analyzed using logistic regression, and a chi square was used to conduct type III effects of fixed effects. With a non-directional alpha risk of 0.05 and assuming a standard deviations of 50.3 mm, the power to detect a difference of ±30 mm in VAS pain would be 0.90 with 60 subjects per group.

10

Chapter 3: Results

Table 1 illustrates that initial pain, age, weight, and antibiotic use were not

significantly different variables between the two groups. All patients presented with

moderate to severe pain on a 170 mm Heft Parker VAS. There was no significant

difference between groups in relationship to preoperative pain levels (p=0.2268).

Furthermore, there was no significant difference between the placebo and steroid groups

with regard to the age of the population sampled (p=0.3786). Weight and the incidence

of taking preoperative antibiotics were not significantly different between groups. Tooth location and tooth type were also not significantly different.

Table 2 demonstrates the gender distribution of the population. There were more females, 61%, than males, 39%. However, there was no difference in regard to gender distribution between the placebo and steroid groups (p=0.3226).

Table 3 breaks down the different preoperative analgesics that were taken by patients, and compares them by experimental group. There was no significant difference between the types of preoperative analgesics used between the groups (p=0.4605).

Table 4 shows injection pain ratings on a 170 mm Heft-Parker VAS during the three phases of injection: insertion, placement, and deposition. The data was divided into

11

maxillary infiltration and mandibular IANB. There was no significant difference

between the groups for any phase of either injection type (p=1.000).

Table 5 illustrates treatment pain during dentin penetration, pulp chamber access,

and instrumentation. Treatment pain between the placebo and steroid groups showed no

significant difference for the three phases of treatment (P=1.0000: dentin, 0.7196: pulp

chamber, 1.0000: instrumentation).

Table 6 demonstrates the pain levels as related by a 170 mm Heft-Parker VAS by day between the groups. In both groups, the number of patients reporting moderate to severe mean pain decreased by day. The mean amount of pain also decreased in both groups by day. By day 4, both groups reported mean pain of none to mild levels. There was no significant difference between the two groups with regard to pain levels by day.

Figure 1 relates to Table 6. The steroid group had lower mean pain scores (however not statistically significant) days 1, 2, 3, and 4, but by day 5 the groups converged. Pain continued to decrease on days 6 and 7 regardless of group. Eighteen teeth had purulent drainage upon access. Nine were in the placebo group and nine were in the steroid group.

Table 7 breaks down swelling status as reported by the patients as better, worse, or the same. There was no significant difference between the groups.. By day 6, none of the placebo group reported their swelling as worse, and 97% of the steroid group reported their swelling status as better or same.

Table 8 and 9 show the analgesic use between groups by day. In Table 8, analgesic use included ibuprofen or the escape medication. A significant difference

12

existed between groups on day 2 and day 3. On day 2, the placebo group took significantly more analgesic medication than the steroid group (p =0.0181). Similarly, on day 3, the placebo group took significantly more analgesic medication than the steroid group (p=0.0147). Day 4 showed near significance, with the placebo group taking more analgesic medication (p=0.0777). By day 5 and continuing through day 7, there was no significant difference in analgesic use between groups. Figure 2 coincides with Table 8.

Figure 2 shows an increase in analgesic use from days 1 to 2 in both groups. Analgesic use declined or remained low for days 2-7.

In Table 9 analgesic use only included ibuprofen. A significant difference existed between groups on day 2 and day 3. On day 2, the placebo group took significantly more ibuprofen than the steroid group (p =0.0055). Similarly, on day 3, the placebo group took significantly more ibuprofen than the steroid group (p=0.0209). By day 4 and continuing through day 7, there was no significant difference in ibuprofen use between groups.

Figure 3 coincides with Table 9. Figure 3 shows an increase in ibuprofen use from days

1 to 2 in both groups. Ibuprofen use declined or remained low for days 2-7.

Table 10 illustrates escape drug utilization by day between the groups. In both groups, escape medication use declined following day 3. The placebo group took the escape medication more than the steroid medication on days 1 through 6. However, this was not statistically significant (p=0.0924). The overall percent of patients taking the escape medication was 24%. Twenty-nine percent of the placebo group and 20% of the steroid group took the narcotic pain medication.

13

Table 11 demonstrates the success by day between the two groups. Success was defined as no to mild pain, 54 mm or less on the 170 mm VAS scale, and no escape medication use. By day 6, both groups had greater than 90% success. However, the overall success was 48% for the placebo group, and 49% for the steroid group. There was no significant difference between the two groups with regard to success (Table 12).

Figure 4 coincides with Table 11, showing that overall success increased from day 1 to day 4 regardless of the group.

Table 12 represents the variables that influence success. The success with regard to group was not statistically significant (p=0.1058). However, the success based by day was highly significant (p<.0001). When factoring the interaction of group by day, there was no significant difference on success (p=0.9171). The only factor that influenced success according to Table 12 was postoperative day.

14

Chapter 4: Discussion

The purpose of this study was to determine if a high dose of methylprednisolone

would help to control postoperative pain and limit analgesic medication use for one week

following root canal debridement of a symptomatic tooth diagnosed with pulpal necrosis.

Tables 1-11 summarize the findings.

Preliminary Data

Table 1 shows the initial pain between the groups. Every subject had moderate to

severe pain recorded on a 170 mm Heft-Parker VAS (22). The data shows that there was

no significant difference between the groups with regard to preoperative pain levels

(p=0.2268). Some authors have related higher preoperative pain levels to higher

postoperative pain levels. (24, 25, 26, 27) Ali et al. found that the presence of

preoperative pain is the variable that most influences the prevalence of postoperative pain

(p<0.001(24). Postoperatively, they recorded pain levels at 4, 8, 16, 24, 48, and 72 hours

on a 0-10 scale. In addition, Genet et al. showed a correlation between postoperative pain

and the presence of preoperative pain in conjunction with a non-vital pulp and the

presence of radiolucency larger than 5 mm in diameter (25). Four hundred forty-three teeth were included and thirteen factors were evaluated in their relation to postoperative pain: dentist type, sex, age, tooth type/position, number of roots, preparation level, obturation level, exudation, periapical radiolucency, preoperative pain, and pulpal status.

15

Other than the presence of a large radiolucency, none of the prior listed variable

contributed to postoperative pain. Law et al. found that the most common predictor of

postoperative pain included preoperative pain and a diagnosis of symptomatic apical

periodontitis with no difference based on pulpal diagnosis (26). Torabinejad studied the effects of multiple medications on postoperative pain following endodontic debridement for up to 72 hours. He found that subjects with high preoperative pain levels had higher postoperative pain levels (27). Sadaf and Ahmad agreed with the above studies, and found that preoperative pain was significantly associated with higher postoperative pain.

(28)

Conversely, Marshall and Liesinger (29) showed that other than the absence of periapical radiolucency, no other factor contributed to an increase in postoperative pain.

The factors studied were: pretreatment pain, age, sex, procedure (instrumentation or obturation), and pulp status. Also, Gomes et al. (30) found that no dental variable predicted the occurrence of postoperative pain.

In this study, only patients who were experiencing moderate to severe pain were selected. This was to minimize the variable that patients without preoperative pain would have less pain postoperatively. If patients were included who did not have pain, the effectiveness of the methylprednisolone would be questioned because, according to Ali,

Genet, Law, and Torabinejad, the patients would have had a lower level of pain from day

1 regardless of the medication.

16

In accordance with Law et al. and Genet et al., the only teeth that were included in

our study were symptomatic teeth diagnosed with pulpal necrosis. This made patients

more likely to have postoperative pain, and in turn, would be a good population to test the

efficacy of steroids in reducing postoperative pain.

Table 1 also shows that there was no significant difference in the age of the

sample between the two groups (p=0.3786). The age range was 18-65 years. Multiple authors have found that age was not a factor in postoperative pain (24, 25, 26, 29, 30, 31,

32). Tighe et al. conducted a hospital study to determine factors associated with postoperative pain following different surgical operations. It was found, while pain decreased each day for all age groups, it decreased more rapidly in the 21-39 year age group. While not significant, the study did show a higher level of pain in the younger age group, age 21-39 (33). Since there was no difference in age between the groups, this variable’s effect was minimized. Patients younger than 18 were not included in this study due to the inability to give consent, and patients greater than age 65 were excluded to eliminate the changes in pain perception as we age. (34). Gibson found that as we age our tolerance for pain increases as our pain threshold increases. Gibson states an explanation for this may be reduced substance P and CGRP in older individuals. In addition Harkins and Chapman found men and women over age 70 had an increased tolerance for pain (35).

In Table 1, the number of patients who presented taking preoperative antibiotics

prescribed from either an emergency department or a dentist is shown. There was no

significant difference between the groups for people taking preoperative antibiotics 17

(p=0.3316). Many authors have suggested that antibiotics play a role in postoperative

endodontic pain. Torabinejad reported erythromycin, penicillin, and a combination of

methylprednisolone and penicillin significantly reduced postoperative pain. However

that study was not well controlled, and the medications may have been given for a vital

tooth (36). Keenan et al. concluded, in a Cochrane review, that there is no evidence to

support the use of antibiotics for pain relief in teeth with irreversible pulpitis (37). Nagle

et al. saw 40 emergency patients with a clinical diagnosis of symptomatic irreversible

pulpitis. Patients received either penicillin or placebo. No endodontic treatment was

performed and patients were given a 7-day diary to record postoperative pain and

medication intake. The administration of penicillin did not significantly reduce patient

reported pain (38). Henry et al. found there was no difference in postoperative pain using

penicillin for symptomatic patients diagnosed with pulpal necrosis compared to a

placebo(39). In a cochrane review, Cope et al. suggested that there is insufficient

evidence to make any conclusion on the effects of antibiotics on postoperative pain in

symptomatic teeth diagnosed with pulpal necrosis (40). In a study by Pickenpaugh et al.,

they found that prophylactic administration of amoxicillin had no effect on the incidence

of endodontic flare-up in asymptomatic patients diagnosed with pulpal necrosis (41).

Mata et al. found that the use of prophylactic pencillin on asymptomatic teeth diagnosed with pulpal necrosis decreased the incidence of postendodontic flare up (42), and

Alsomadi et al. reported that taking a regimen of augmentin along with ibuprofen significantly reduced pain and analgesic use 48 hours following root canal therapy

18

compared to ibuprofen alone. Unfortunately, Alsomadi et al. did not differentiate the pulpal status of the cases studied (43).

Most endodontists agree that antibiotics have no impact for teeth diagnosed with symptomatic irreversible pulpitis. In addition, most endodontists agree that the routine prescription of antibiotic use for teeth diagnosed with pulpal necrosis is not warranted.

The widely accepted use of antibiotics for endodontic treatment is when cellulitis or acute abscess is present (44). Because no patients in our study presented or developed cellulitis or acute abscess, there was no need to prescribe antibiotics. There does not appear to be a consensus among authors regarding the ability for antibiotics to decrease postoperative pain, but the clinical consensus is that they have no bearing on postoperative pain. If clinicians feel that antibiotics may play a role in controlling or eliminating postoperative pain, our study minimized this effect. The distribution of patients taking a preoperative antibiotic regimen was not different between the two study groups.

Table 2 shows the gender distribution between and among the groups. Thirty two (39%) of the subjects were male and 51 (61%) were female. Among the placebo group, 14 were male and 28 were female. In the steroid group, 18 were male and 23 were female. The chi square test showed us there was no statistically significant difference between the two groups for gender distribution (p = 0.3226). This is important because gender has been shown to affect reported postoperative pain in endodontics. Ali et al. found that females reported significantly more pain up to 72 hours postendodontic treatment (24). Gotler et al. also found that postoperative pain after root canal therapy 19

was higher in women up to 18 hours following treatment (45). Sadaf and Ahmad found that 65% of females reported postoperative pain compared to only 35% of males (28).

Fox et al. and Genet et al. agreed with the above authors that females reported higher pain levels than males (25, 31). However, some authors have found that there was no difference between genders (26, 29).

We had no significant difference between groups with regard to gender. Patients were randomly assigned to groups with no regard for gender. Due to the random assignment, we could have had more of one gender in a certain group, but because this did not occur the effects of gender were minimized.

Another factor that may affect postoperative pain may be the use of preoperative pain medications. Table 3 illustrates the distribution of the patients who were taking preoperative analgesic medication within 8 hours prior to inclusion in the study. Patients were questioned on their analgesic use and the reported medications were; NSAIDs, acetaminophen, narcotics, and NSAID/acetaminophen combinations. The most common response was no preoperative analgesic use. This response constituted 58% of the placebo group and 43% of the steroid group. The second most common response was

NSAIDs. Thirty two percent of the placebo group and 27% of the steroid group reported taking a preoperative NSAID. Fourteen percent of the steroid group reported narcotic use compared to 5% of the placebo group. The next common analgesic medication was acetaminophen, and the least common was a combination of NSAID and acetaminophen.

A Fisher exact test was used to evaluate the significance of this distribution and no significant difference was present (p = 0.4605) between the groups. 20

We evaluated preoperative pain medication use because patients who took pain

medication prior to presenting to the clinic for treatment may be more likely to take pain

medication during the postoperative period. While this does not tell us about the amount

of pain the subjects presented with, it does tell us that some patients are more abstinent of

analgesic medications than others. Subjects were not assigned to a group based on their

medication use. Because there was no statistically significant difference between the

two groups with regard to preoperative analgesic use, and initial pain ratings, the effect of

some patients abstaining from analgesic use preoperatively were minimized in this study.

Finally, by the time patients were recording their pain levels on day 1, any preoperative

pain medication that the patients had taken would have been metabolized and excreted

and no longer active. Therefore, the preoperative medication used would have no effect

on the pain rating during the postoperative period surveyed. The preoperative analgesic

use could potentially give us insight into the pain tolerance of each group. Perhaps since

the steroid group had a higher percentage of preoperative analgesic use, this group had a

lower pain tolerance? However we would expect this to correlate to higher measures on

the initial VAS, and the subsequent injection and treatment VAS. This was not observed.

Injection Pain

Table 4 illustrates injection pain between the groups. There was no significant difference between the groups for any injection phase (p = 1.0000). For the maxillary infiltration, needle insertion was the least painful with the mean pain being less than mild on the 170 mm VAS. Needle placement pain was higher than needle insertion pain, but the mean was still less than mild. Solution deposition was the most painful phase of the 21

injection. For the inferior alveolar nerve block, needle insertion was the least painful

with the mean pain being less than mild on the VAS. Needle placement pain was higher

than insertion pain for both groups. Solution deposition was the most painful phase of

the injection for both groups. Both groups had a mean pain greater than mild, but less

than moderate on the VAS. Also apparent in Table 4, are the wide ranges of standard

deviation for all injection phases. This tells us that regardless of injection type or phase,

all injections had a high variability and a likelihood to cause pain.

Glenn et al. studied anesthetic injection pain in symptomatic teeth diagnosed with

pulpal necrosis during maxillary infiltrations and inferior alveolar nerve blocks (IANBs).

The highest pain during the three phases of injection occurred during solution deposition

and needle placement for maxillary infiltration and needle placement for the IANB (2).

Wells et al. studied injection pain on symptomatic teeth diagnosed with pulpal necrosis.

He reported that during IANB more patients reported moderate-severe pain during needle insertion, needle placement, and solution deposition than the patients receiving maxillary infiltration injections (46). Sebastian et al. reported the most painful phase of injection was needle insertion and solution deposition, but injection type was not distinguished (1).

Dental local anesthesia injections have the potential to be painful especially in patients presenting with pain. Nusstein and coauthors concluded that in asymptomatic patients the most painful phase of an IANB is the needle placement (23). In our study, there was little difference between the needle placement and solution deposition phase.

Also, patients were given the injection and then recorded pain levels following the injection. This method may have caused a blending of pain among the three phases. The 22

patients may not have been able to adequately differentiate between the three phases of injection due to them all being recorded at one time. This may be especially apparent from the needle placement to the solution deposition phase. Our study also showed a high variability in reported injection pain with standard deviations being anywhere from

23-61 mm from the mean. This tells us our study agrees with previous studies on injection pain, that regardless of the phase or type of injection, there is potential for pain.

We found no significant difference in injection pain for either the IANB or maxillary infiltration with regard to experimental group. There was no statistically significant difference between the groups with regard to pain recording of the injection.

Because the injections caused pain, this demonstrates that there was no difference between groups with regard to pain perception and recording. This is important because pain was recorded daily, and if one group constantly reported higher pain levels the results could be inaccurate.

Treatment Pain

Table 5 shows treatment pain at three phases between the groups. There was no significant difference in treatment pain for any phase of treatment between the groups.

The first phase was when dentin was encountered, and both groups reported less than faint pain. The median value was 0 which shows us that there was very little pain at this phase. The second phase was when the pulp chamber was accessed. The pain levels were slightly higher than the dentin phase, but the mean pain was still less than faint and the median was 0 as well. The most painful phase of treatment was shown to be

23

instrumentation. The pain was still classified as faint to weak for both groups and the

mean was 25 mm for the placebo group and 23 mm for the steroid group. When the grade

of anesthesia was evaluated, 65% percent of the patients had profound anesthesia, 22%

were numb but still had some discomfort, 1% were not numb and refused additional anesthetic, and 11% were not numb and were given supplemental anesthetic. This anesthesia grade was a subjective measure that was completed by the operator (M.F.)

Five patients in the maxillary group needed supplement anesthesia and four patients in the mandibular group needed supplemental anesthesia.

This data agrees with the results of Sebastian et al. and Wells et al. Both authors found that the most painful aspect of treatment of symptomatic teeth diagnosed with

pulpal necrosis was instrumentation. Sebastian and co-authors reported that 35% of

patients experienced moderate pain while 3% reported severe pain during this phase of

treatment (1). Wells and coauthors reported that 34% reported moderate pain while 4%

reported severe pain (46). In our study we only had 20% that reported moderate pain, and

no patients reporting severe pain during instrumentation. The difference in moderate to

severe pain may be best explained by operator and instrumentation method. The absence

of pain during dentin access and pulp chamber access could be expected since there is the

lack of innervation of those structures due to the diagnosis of pulpal necrosis. If there is

no pulpal innervation, and no stimulation of the periodontal tissue, no pain should be

perceived during the first two phases of treatment. The pain during instrumentation could

be explained by the anesthetics, potential inability to completely anesthetize the apex and surrounding periradicular tissue. Periapical inflammation is a complex process and the

24

inflammatory cells present may prevent the ingress of the local anesthetic into the

periapical area. (44,49) Therefore, when instrumenting the canals, if fluid or debris is

extruded into the periapical area a patient could have an increased pain experience.

Another possible explanation is hyperalgesia. Insult to the dental pulp complex has been

shown to increase neuropeptides CGRP and substance P (47) as well as extensive

sprouting of sensory nerve fibers (48). With so many inflammatory cells present in the

periapical area along with nerve sprouting, a lower pain threshold may be present and

create a feeling of hyperalgesia in which the local anesthetic cannot overcome the altered

resting potential. In addition, allodynia may account for a perception of pain during instrumentation. During instrumentation, torsional forces may be transferred to the root.

While this would normally not be a painful sensation, with the increased inflammation at the apex and in the surrounding periodontal ligament, this is perceived as a painful stimulus.

Steroids

The adrenal cortex produces substances known collectively as corticosteroids. As a whole, corticosteroids are generally referred to as steroids. These corticosteroids are

further divided into glucocorticoids and mineralocorticoids. Glucocorticoids have a

greater effect on carbohydrate metabolism, while mineralocorticoids enhance sodium

retention and possess no anti-inflammatory effects. Glucocorticoids possess potent anti-

inflammatory actions. They induce the production of lipocortin, which inhibits

phospholipase A2. The inhibition of phospholipase A2 decreases the production of

arachidonic acid. Arachidonic acid normally will go on to produce leukotrienes and 25

prostaglandins, potent inflammatory mediators. Thus, by limiting arachidonic acid, those

potent inflammatory mediators are decreased. Glucocorticoids also have a direct effect on

cyclooxygenase, which will limit prostaglandin synthesis even further. These actions will produce a net result of inhibition of neutrophil, eosinophil, and monocyte chemotaxis, inhibition of capillary permeability and bronchoconstriction. Finally, glucocorticoids hinder the attachment and recruitment of these inflammatory cells to the site of inflammation. (50) With these potent anti-inflammatory actions, it would be reasonable to expect a decrease in pain following root canal therapy for symptomatic teeth diagnosed with pulpal necrosis.

A number of glucocorticoid preparations exist. They vary based on biologic half-

lives as well as route of administration. Natural hormone, hydrocortisone, tends to have

less potency and a shorter half-life than the synthetic glucocorticoids. Glucocorticoids can be divided into short acting (less than 12 hours), intermediate acting (18-36 hours), and long acting (36-72 hours). The biologic half-life of a glucocorticoid is based on the period of suppression of the HPA axis. Short acting glucocorticoids include cortisone and hydrocortisone. Intermediate acting glucocorticoids include methylprednisolone, prednisolone, prednisone, and triamcinolone. Long acting glucocorticoids include betamethasone, dexamethasone, and paramethasone. In addition, the intermediate and long-acting glucocorticoids have a greater ratio of glucocorticoid to mineralocorticoid activity which makes them more beneficial for long-term use of chronic inflammation due to less disruption of the electrolyte balance. (50)

26

Glucocorticoid Pharmacodynamics

Glucocorticoids are well absorbed in the gastrointestinal tract and have a

bioavailability of 60-100%. When focusing specifically on methylprednisolone, 82-91%

of oral methylprednisolone is available for absorption (51). Methylprednisolone has no

affinity for transcortin (51, 52, 54) and binds only to albumin. Accordingly

methylprednisolone pharmacokinetics are linear. (51, 53). Oral methylprednisolone

reaches its peak plasma concentration in 2.1 +/- .7 hours with a peak plasma concentration of 8.2 +/- 2.4 ug/L/1mg dose. (51)

Czock et al. discussed the benefit of a twice daily dose vs. a once daily dose of methylprednisolone. Due to the short half-life of methylprednisolone, 2.5 +/- 1.2 hours,

(51) concentrations fall to below their concentration of half-maximal effect (CE50) within 12 hours after administration. It has been suggested that a twice daily dose will maintain the therapeutic dose throughout the day better than a once daily dose. This may allow the methylprednisolone to have a greater effect and also allow a lower total daily dose. Czock et al. created a model to study the therapeutic effects. It was found that the twice-daily administration had a greater total effect despite the same total dose. It was also found that administration of twice-daily dose fractions increased the immunosuppressive efficacy of methylprednisolone while it did not increase short-term adverse effects, except for endogenous cortisol (51). The twice daily dose is discussed later and its relationship to our study.

27

Adverse Effects

Glucocorticoids have many valuable applications, but they also have the potential for severe complications. The frequency and severity of these complications are correlated with dose and duration of treatment. Some complications include: neurologic

(insomnia, agitation, and mania), infectious (increased occurance of opportunistic infections), vascular (hypertension, increased atherosclerotic disease risk), skin and mucosa atrophy, skeletal (reduced Ca absorption, osteoporosis, avascular osteonecrosis, impaired growth), muscular (myopathy, wasting), metabolic (glucose intolerance, obesity, hyperlipidemia), reproductive (hypogonadism), gastrointestinal (peptic ulcer), and ocular (cataracts). These side effects are typically the result of a predisposing condition or long term use. A final complication is the suppression of the hyptothalamic- pituitary-adrenal (HPA) axis. However, dosing of 1 week or less does not appear to cause any significant suppression of pituitary or adrenal function. (50).

With regard to HPA axis suppression, Zora et al. studied HPA axis suppression after short-term, high dose glucocorticoid therapy in children. The authors concluded that a high dose (max of 60 mg/day) produced only transient HPA axis suppression and all corticosteroid responses were normal 10 days after completion of the drug course (55).

Wenning et al. studied the recovery of the HPA axis from inhibition by short-term, IV, high-dose, corticosteroid therapy without subsequent oral replacement. One thousand mg of prednisolone was given for 5 consecutive days. The authors showed significant HPA axis suppression 24 hours after discontinuing the corticosteroid. However, rapid recovery followed with higher than baseline levels occurring at 48 hours. Mean basal 28

adrenocorticotropic hormone and cortisol concentrations returned to normal within 120

hours. The authors concluded that high doses of corticosteroids without oral replacement

was “endocrinologically” safe (56). Williamson et al. showed that with a single dose of

8 mg dexamethasone, there was an initial suppression of the normal feedback mechanism

of the hypothalamic-pituitary-adrenal axis followed by a complete return of normal

function by the seventh postoperative day (57). Based on these studies, we did not expect

the HPA axis to be suppressed enough to justify the use of a tapering dose. Therefore we

did not use a tapering dose in our study.

Dose

In our study, we gave a higher dose of steroid than is normally given for pain.

With an increase in dosage, there may also be an increase in the side effects that were

mentioned earlier. Many authors have conducted studies that included a high dose of

methylprednisolone (11-21, 58). These studies are detailed below. They provide a

positive justification for increasing the dosing to a total of 336 mg throughout the 6 day

period with low risk of an adverse effect.

Weigelt et al. and Meduri et al. studied the use of high dose methylprednisolone

in patients with respiratory distress and respiratory failure. Weigelt et al. gave 30 mg/kg

of methylprednisolone every 6 hours for 48 hours. The authors reported no significant

increase in infectious complications compared to the placebo (11). Meduri et al. studied

a 2 mg/kg dose of methylprednisolone for 32 days. Similar to Weigelt et al. they showed

there was no increase in infection rate compared to a placebo (12).

29

Sprung et al., Bone et al., and Schumer et al. studied the use of

methylprednisolone in patients with septic shock. Sprung et al. gave either 30 mg/kg of

methylprednisolone, 6 mg/kg of dexamethasone, or a saline placebo. While the

administration of the steroid did not improve the survival rate of patients, there were no

increased complications (13). Bone et al. administered a 30 mg/kg dose of methylprednisolone 4 times in patients with septic shock. They did report a higher risk of secondary infection with this high dose (14). Schumer et al. studied a dose of 3 mg/kg of

dexamethasone, 30 mg/kg of methylprednisolone, or a saline placebo in patients with

septic shock. They reported that the steroids significantly reduced mortality, and there

was no significant difference in complications between the placebo and the steroids (15).

Walmsley et al. studied a 40 mg twice-daily dose of methylprednisolone for 10

days. The patients studied were diagnosed with AIDS who had Pneumocystis carnii

pneumonia. Walmsley et al. concluded there was no increased risk of superinfection

compared to the placebo group (16).

Waldron et al. and Nagelschmidt et al. related high doses of methylprednisolone to potential postsurgical complications. Waldron et al. conducted a systematic review and meta-analysis. Included were studies that gave 1.25 – 20 mg of dexamethasone in an

I.V. form prior to surgery. They concluded that the dexamethasone dose decreased pain

and opioid use with no increased risk of infection or delayed wound healing (17).

Nagelschmidt et al. studied the use of I.V. methylprednisolone prior to abdominal

surgery. Thirty mg/kg was given in a one-time dose, and it was shown to decrease hospital stays with no major side effects occurring (18). 30

Oliveri et al. and Sellebjerg et al. studied the use of high dose methylprednisolone in patients suffering from multiple sclerosis. Oliveri et al. compared a 2 g I.V. dose for 5 days or a 500 mg I.V. dose for 5 days. The higher dose significantly reduced lesions visible by magnetic resonance imaging with no major side effects (19). Sellebjerg et al., in a double blind study, compared a 500 mg dose of methylprednisolone for 5 days followed by a 10 day taper period to a placebo. The authors concluded that it helped for up to 8 weeks when compared to the placebo. No serious adverse events occurred (20).

Sellebjerg et al. conducted a follow up study to the above by studying the same dose and its effect on acute optic neuritis. A 500 mg dose of methylprednisolone was given for 5 days and was followed by a 10 day taper period. This dosing was shown to help speed recovery compared to a placebo, but there was no difference at 8 weeks (21).

Friedli et al. studied a 250 mg I.V. dose of methylprednisolone twice a day for 3 days in patients with alopecia. No major side effects were reported with the dose, and it helped treat a rapidly progressing form of alopecia (58).

As illustrated above, many authors have conducted studies with a high dose of methylprednisolone. The majority of these authors found no increase in adverse events when the high dose was given and the ones that did show an increase in infection rate were in patients who were not healthy when beginning the study (59). The dosage studies varied from 2 mg/kg up to 30 mg/kg for an extended period of time. In our study, the subjects’ median weight was 170 lbs. When our median weight is factored in, at 2 mg/kg, this dose is equivalent to 154 mg, and at 30 mg/kg the dose is equivalent to 2310

31

mg. The total dose that was given of methylprednisolone is our study was 336 mg over a

6 day period. Based on the dosage given in the previously mentioned studies, the dosage

of 96 mg on day 0 followed by 48 mg for 5 days did not result in significant adverse effects, and was, therefore, warranted and safe.

Steroids and Dentistry

Glucocorticoid use in dentistry is not new. Many oral ulcerations can be treated by topical glucocorticoids. The relief of symptoms and accelerated healing have been

reported (50). Conditions that may benefit from topical treatment include; traumatic

ulcers, aphthous ulcers, erosive lichen planus, erythema multiforme, pemphigus,

desquamative gingivitis, and angular stomatitis (50). A second use in dentistry, is for

temporomandibular joint disorders with intra-articular injections of a glucocorticoid.

This will typically give a short term resolution of symptoms unless the underlying cause

is corrected. However, it has been speculated that bony deterioration may occur following

intra-articular injection of a glucocorticoid. (60). Glucocorticoids have also been used to

treat postoperative edema and trismus following surgical procedures. (61-67)

Specific formulations and applications that have been studied in dentistry are detailed below. Intracanal prednisolone was studied by Chance et al. (5), Moskow et al.

(3), and Jalazade et al (68). Dexamethasone has been studied in a supraperiosteal (69, 70,

71), oral (61, 62, 64, 66, 72-75), and intramuscular route (65, 77, 78). Triamcinolone was

studied by Negm et al. as an intracanal application (4). Methylprednisolone has been

32

studied via an oral route (10, 61, 62), an intraosseous route (7, 8, 9), a submucosal route

(63), and finally as an intraligamentary injection by Kaufman et al (6).

Specific to endodontics, studies have been conducted to evaluate the use of

glucocorticoids for postoperative pain. However, not many studies have only focused on

symptomatic teeth with a pulpal diagnosis of necrosis.

Postoperative Pain

In this study, patients recorded their post-endodontic pain levels on a 170 mm

VAS for 7 days, and the results are shown in Table 6. On day’s 1-7 there was no

significant difference between the groups. The biggest difference in mean pain levels

was day 1. The steroid group reported their mean pain to be 34 mm compared to the

placebo whose mean pain level was 55 mm. Figure 1 illustrates that the placebo group

had more pain on days 1-4, but by day 5 the pain levels were similar. On day 1, 60% of

the placebo group reported none to mild pain while 36% had moderate pain and 5% had

severe pain. In the steroid group, 70% reported none to mild pain while 28% had

moderate pain and 3% had severe pain. Even though the pain levels were lower for the

steroid group on day 1, the pain ratings were still relatively high with 30% reporting

greater than mild pain. On day 2, the patients in the placebo group reporting none to mild

pain increased to 69%. Patients in the steroid group stayed the same, 70% reported none

to mild pain. Both groups had a decrease in patients reporting severe pain. Also on day

2, the placebo groups’ mean pain level decreased from 55 mm to 38 mm, and the steroid

group dropped from 34 mm to 31 mm. By day 3, both groups had a mean pain level

33

below weak on the VAS. Only 1 patient in the placebo group, and none in the steroid group, reported severe pain for the remainder of the surveyed days. By day 4, 90% of the patients in the steroid group had less than mild pain. For the placebo group on day 4,

88% reported less than mild pain, and by day 5 this jumped to 95%. By day 4, the mean pain levels in both groups were less than faint on the VAS.

The results demonstrate that regardless of the medication given, the patient’s pain significantly improved each day. This agrees with studies by Glenn et al., Sebastian et al., and Wells et al. (1, 2, 46). In a study comparing pain levels in symptomatic teeth diagnosed with pulpal necrosis, Glenn et al. found that patients reported mean pain as less than mild on a VAS by day 3, regardless of liposomal bupivacaine injection or bupivacaine injection (2). Sebastian et al. saw similar results. Sebastian and coauthors compared pain level following debridement versus non-debridement of symptomatic teeth diagnosed with pulpal necrosis. In the debridement group, mild pain was achieved by day 1 and improved throughout the 5 surveyed days. Even if no debridement was completed, patients reported mild pain by day 3 (1). Wells et al. also studied symptomatic teeth diagnosed with pulpal necrosis. The authors studied the use of a combination of ibuprofen/acetaminophen and compared it to ibuprofen use and its effect of postoperative pain. The authors found that by day 3 the mean pain level on the VAS was less than mild regardless of the postoperative medication that was given (46).

The above studies support our findings. We found that by day 2, the mean pain levels were less than mild on the VAS for both groups and continued to decrease throughout the surveyed days without a rebound. In a similar study, Claffey et al. gave a 34

lower dose, 48 mg, of oral methylprednisolone for only 3 days. He reported that after the

patient stopped taking the steroid medication there was a rebound effect with pain levels

increasing on days 4 and 5 (10). It can be hypothesized that by day 3, a large number of

inflammatory mediators are still present and they can cause an increase in pain once the

steroid is stopped. The extension of methylprednisolone to day 5 and increasing the dose may have eliminated this rebound effect. However, it is unknown if it is an effect of the number of days taking the steroid, the dose, or a combination of the dose and timing. We had no patients rebound in our study.

We had one patient who was enrolled in the study twice for the same tooth. There was 6 months between visits, and the code was broken to ensure this patient received the opposite medication than was used the first time he was enrolled. This patient experienced lower day 1 pain when taking the steroid, but days 2-6 his pain levels were

higher when taking the steroid compared to the placebo. When he was taking the steroid,

his pain levels were moderate on days 2, 3, and 4, but when he was taking the placebo he

had no moderate to severe pain throughout the surveyed period. While we cannot make

any conclusions from this one patient, it is an interesting comparison to show that the

steroid had no effect on his postoperative pain.

Postoperative Pain and Methylprednisolone

Methylprednisolone has been studied by multiple authors for use in postendodontic pain. As discussed earlier, Claffey et al. evaluated the effects of an oral dose of 48 mg of methylprednisolone, taken each day for three days, on postoperative

35

pain in symptomatic teeth with a pulpal diagnosis of necrosis. Thirty-four patients were included. Following complete endodontic debridement, patients were divided up into two groups, 48 mg of methylprednisolone taken for three days or a placebo.

Postoperatively, patients received ibuprofen, Tylenol #3, and a diary to record pain and medications taken. The authors found that methylprednisolone reduced pain and the use of pain medication for the first 3 postoperative days when compared to the placebo.

However, on the day of endodontic treatment, and on days 4 through 7, patients still had moderate or severe pain, or took a large number of analgesic drugs. The authors theorized that the initial dose of methylprednisolone was too low and had worn off later in the week resulting in a rebound of inflammation and pain (10). Our data shows that increasing the dose to 96 mg followed by 5 days of 48 mg eliminated this rebound effect, but was not completely effective at eliminating pain similar to the placebo.

Kaufman et al. studied the use of methylprednisolone as an intraligamentary injection (6). Forty-five patients participated in the study with no exclusion as to pulpal diagnosis. Patients were divided into three groups. Group 1 received 4 mg of slow- release methylprednisolone (Depo-Medrol) or 8 mg of the same medication as a periodontal ligament injection around the affected tooth. Group 2 received an active placebo of 3% mepivacaine. Group 3 received only anesthesia necessary for endodontic therapy. In groups 1 and 2, the medication was injected immediately after anesthesia onset, and before the rubber dam was placed. Following rubber dam placement, endodontic treatment was completed. Of the teeth treated, 22% were vital, 9% had acute pulpitis, 3% were chronic pulpitis, 32% were necrotic (either symptomatic or

36

asymptomatic), 4% had a combination of necrosis and pulpitis, and 29% were

retreatments. A significant decrease in postoperative pain was found in the

methylprednisolone group compared with the other two groups. Furthermore, the

authors showed that teeth with necrotic pulps and endodontic retreatments had the highest

incidence of postoperative pain (16% and 13%). There was no data that suggests the

necrotic and retreatment teeth had less pain with methylprednisolone. Their study

conclusion was that the methylprednisolone significantly reduced the frequency and

intensity of postoperative pain. However, significance was not broken down by pulpal

diagnosis and may have been underpowered.

Gallatin et al. and Bane et al. both showed that intraosseous injection of

methylprednisolone reduced postoperative pain in untreated teeth diagnosed with

symptomatic irreversible pulpitis. (7,8). Gallatin et al. had 40 subjects. After local

anesthesia was obtained, a 40 mg intraosseous injection of Depo-Medrol or 1 ml of sterile

saline was administered. No endodontic treatment was initiated. Following treatment,

patients were given a 7-day pain diary and given twenty 600 mg ibuprofen tablets and

twenty tablets of Tylenol #3. Patients were instructed to only take the Tylenol #3 if the

ibuprofen did not alleviate their pain. The methylprednisolone group had significantly

less pain post-injection from days 1-7 compared with the placebo, and took significantly

less pain medication.

In a similar study, Bane et al. included 94 patients that had symptomatic irreversible pulpitis (8). Patients were divided into two groups. Group 1 received an emergency pulpotomy and group 2 received an intraosseous injection of 40 mg of Depo- 37

Medrol. Patients were given both 400 mg ibuprofen tablets and codeine/acetaminophen

30mg/500mg. Patients were also given a 7-day pain journal to record pain and medication use. At the end of the 7 day period, definitive treatment was provided.

Patients were recalled at 6 months to evaluate the status of the tooth. Patients in the methylprednisolone group reported less intense spontaneous and percussion pain from day 0 to day 7 than the pulpotomy group. There was no difference in outcome at 6 months.

Bramy et al. studied the effects of a 40 mg intraosseous dose of slow-releasing methylprednisolone (Depo-Medrol) in symptomatic teeth diagnosed with pulpal necrosis.

Thirty-eight patients were included. Following endodontic debridement, subjects either received an intraosseous injection of 40 mg Depo-Medrol or 1 ml of sterile saline in the same fashion. Subjects received ibuprofen and Tylenol #3 and a 7 day pain diary. The

Depo-Medrol group had significantly less pain and took significantly less pain medication than the sterile saline group. However, moderate to severe pain still occurred in the Depo-Medrol group. The authors felt that the insoluble acetate form of the Depo-

Medrol may have dissolved too slowly, therefore, there was not enough of the drug to be effective (9).

These previous studies on methylprednisolone show positive results for teeth with vital pulps. However, there was not enough data to suggest that methylprednisolone helps in symptomatic teeth diagnosed with pulpal necrosis. Our results with Bramy et al. and Claffey et al. in the fact that the methylprednisolone did not reduce the pain enough to warrant its use. By increasing the dose of steroid and number of days above and 38

beyond what Claffey et al. did, we were able to eliminate the rebound effect, but there was still no significant difference in pain levels when comparing its use to the placebo group. While Bramy et al. found pain was significantly reduced; moderate severe pain was not completely eliminated. This questions the use of steroids.

Many practitioners propose the use of a methylprednisolone dose pack to reduce or eliminate postoperative pain following endodontic therapy. The normal dose of a 4 mg methylprednisolone dose pack is as follows: day 1: 24 mg(6), day 2: 20 mg(5), day 3:

16 mg(4), day 4: 12 mg(3), day 5: 8 mg(2), and day 6: 4 mg(1). Our study dose was as follows: day 0: 96 mg, day 1: 48 mg, day 2: 48 mg, day 3: 48 mg, day 4: 48 mg, and day

5: 48 mg. The much higher dose that we gave to patients following endodontic debridement can be appreciated. The total amount of medication in a dose pack is 84 mg while the total amount that we gave was 336 mg. Without a significant decrease in pain, compared to the placebo in our study, it is unlikely that a dose pack would be an effective pain management tool for postoperative pain following endodontic therapy for symptomatic teeth with a pulpal diagnosis of necrosis.

Perhaps a twice-daily dose would be more effective in pain management. As mentioned earlier, Czock reports that the pharmacodynamics of methylprednisolone support a twice daily dose to maintain the therapeutic dose. Within 12 hours of taking methylprednisolone, it is at half of its maximum effect. If concentrations were maintained by taking a dose every 12 hours, this may have a beneficial effect on the patients pain (51). Czock also states that by giving the methylprednisolone twice daily one may be able to lower the total dosing amount therefore reducing the risk of adverse 39

effects (51). This may be a consideration for a follow-up study. However, it would be

unlikely that even with a twice daily dose we would see a significant difference in pain

levels. We must remember that our studies pain levels compared the dose of

methylprednisolone to a placebo. If we saw a large difference, a twice daily dose may be worth studying. We did not see a large difference and had very little reported side effects. Due to a lack of pain reduction when compared to a placebo in our study, further studies of methylprednisolone are not warranted in a once or twice-daily schedule.

In our study, we only had one patient in the steroid group complain of any trouble

sleeping. We instructed the patients to take the methylprednisolone upon waking. If the

dose is taken twice daily, this second dose may be close to the time the patients are trying

to sleep. While this could potentially decrease their pain, they may not be able to sleep

due to the dosing schedule. Cortisol production is usually highest in the morning and

lowest in the evening and at night. If this normal pattern is effected, the patients sleep

may be disrupted (79). With Czock’s information in mind it is important to discuss the

time the patients in our study were recording their pain. Patients were asked to record

their pain levels upon waking. If patients took their methylprednisolone as instructed, the

time of the pain recording coincided with the lowest effective period of the

methylprednisolone. We can assume that at the time of the pain ratings, it was also the

time of day with the highest pain.

The dose in our study was 4 times higher than a normal dose pack. With an

increase in medication use, the potential for side effects are increased. A notable side

effect of both methylprednisolone and ibuprofen is gastrointestinal distress including the 40

development of a gastric ulcer. In our study, patients were only instructed to take the

ibuprofen if it was needed for pain. Due to the potential combination of the two

medications, patients were screened for a history of previous gastric ulcers. One patient in the steroid group had to stop taking the medication due to stomach pain and was subsequently excluded. She had a prior history of peptic ulcer, but did not disclose this prior to treatment. Also, prior to treatment she was taking a large dose of ibuprofen to control her pain, and stated that the days immediately following treatment she was drinking large amounts of coffee and eating a lot of chocolate. All of the above factors can compound the effects of the ibuprofen and steroid. After this, we asked specific questions to the patients in regard to any history of GI distress to help prevent patients who did not disclose prior problems. If any concern was raised with regard to any possible contraindications, patients were excluded from the study.

Of interest, we only had one patient who stopped taking the study medication due to the way it made them feel. This patient commented in their journal that they stopped taking the medication because “it was affecting my moods and just didn’t agree with me.” This patient was actually taking the placebo. This shows us the power of the placebo effect on a patient’s perception of how they are feeling (80, 81, 82).

Postoperative Pain and Prednisolone

Prednisolone has been studied by Praveen et al. (76), Chance et al. (5), Moskow et al. (3), and Jalazade et al. (68). Praveen and coauthors studied the postendodontic effects of a preoperative oral 30 mg dose of prednisolone. The authors concluded that the

41

prednisolone reduced pain following endodontic treatment at 12 hours, compared to a

placebo and ketorolac. However, when the results were further divided by pulpal

diagnosis, the authors found that the prednisolone was not any more effective than the

placebo at reducing postoperative endodontic pain (76). Chance et al. studied the use of

2.5% prednisolone as an intracanal medicament following endodontic debridement.

Prednisolone was effective in significantly reducing the incidence of postoperative pain

in teeth where vital pulp was present. However, when the pulp was necrotic, the

prednisolone was ineffective in reducing the incidence of postoperative pain after 24

hours (5). Three-hundred patients were treated by either placing the prednisolone or saline in the canal with sterile paper points, and the canals were sealed with Cavit. Pain was recorded immediately postoperatively and 24 hours after treatment. Moskow et al. showed similar results in reducing postoperative pain in vital teeth using an intracanal glucocorticoid; however, this study did not include any necrotic teeth (3). Fifty patients were included and either received an unknown glucocorticoid or saline as an intracanal medication. Pain ratings were recorded for 72 hours after treatment. A statistically significant decrease in pain was present only at the 24 hour time period for the glucocorticoid group. At all other times periods, pain was less, but it was not significantly less with the glucocorticoid group. Jalazade et al. studied the use of a single dose of prednisolone preoperatively in 40 patients with varying pulp status and pain history. Thirty mg of prednisolone or a placebo was given 30 minutes before root canal therapy. The study showed that 30 mg of prednisolone preoperatively significantly reduced postoperative pain at the 6, 12, and 24 hour postoperative time periods. Patients

42

received a rescue medication of ibuprofen or acetaminophen and were instructed to take the medication as needed. If the patients took the rescue medication they were excluded from the study. The results showed that the prednisone group had significantly reduced pain at 6, 12, and 24 hour periods. However, patients presenting with pulpal necrosis experienced more pain than teeth diagnosed with vital pulps at 24 hours in both the placebo and prednisolone group. This study only followed patient pain for 24 hours post operatively (68).

Postoperative Pain and Dexamethasone

Dexamethasone has been studied as a way to reduce postoperative pain by many authors. Shantiaee et al. studied the use dexamethasone on postoperative pain following the initial debridement of teeth with multiple diagnoses. Ninety patients participated and had complete canal debridement of a molar tooth. The patients were then divided into three groups and received a supraperiosteal injection in the buccal vestibule of 4 mg of dexamethasone, 1mg infiltration of morphine, or 1mL normal saline. Patients were then given a rescue medication of 500 mg acetaminophen and a pain journal to record pain levels at 4 ,8, 24, and 48 hours after the appointment. Four mg of dexamethasone by periapical infiltration led to a considerable decrease in pain compared to the placebo following root canal debridement during the first 24 hours. However, no significant difference was noted at 48 hours. It was also observed that the dexamethasone was significantly more effective than morphine in pain reduction. In addition, dexamethasone and morphine were more effective in maxillary teeth compared to mandibular teeth most likely due to the absorption. Pulp status or periapical conditions did not exhibit any 43

significant correlation to postoperative pain (70). Pochapski et al. studied the effect of

pretreatment with 4 mg oral dexamethasone on postendodontic pain of asymptomatic

vital pulps. Forty-seven patients were included. The medication or placebo was given 1

hour prior to endodontic debridement and a postoperative pain survey was completed for

48 hours. The results showed a significant decrease in pain at 4 and 12 hours

postoperatively, but there was no difference at 24 and 48 hours compared to the placebo.

The placebo group exhibited higher rescue medication (750 mg acetaminophen) use (72).

Marshall and Walton studied the effect of an intramuscular injection of

dexamethasone on posttreatment endodontic pain. Fifty patients were selected and

received either 1 appointment or 2 appointment endodontic treatment. At the end of the

first appointment, the patients either received 1ml of dexamethasone or saline. This study

had a mix of pulpal and periapical diagnoses. Pain was recorded at 4, 24, and 48 hrs postoperatively, and showed that the glucocorticoid reduced pain and severity of pain at 4

(significant) and 24 hours (“approached significance”). At 48 hours, there was no

difference between the placebo and dexamethasone. No significant relationship was

shown between pulpal diagnosis, periapical status, age, gender, number of appointments, or tooth number on postoperative pain. The only significant variable was the presence of pain preoperatively which was related to the presence of post-treatment pain (77).

Glassman et al. also studied dexamethasone, but in an oral form. Teeth that were studied included only those diagnosed with asymptomatic irreversible pulpitis.

Forty consecutive patients were selected and endodontic debridement was completed.

Patients were asked to rate their pain at 8, 24, and 48 hours after the treatment. The 44

results showed that oral dexamethasone (12 mg), compared to a placebo, resulted in

significant reduction in postoperative pain at 8, 24, and 48 hours compared to the

placebo. Patients were excluded from the study if they took any oral analgesics. (73).

Krasner and Jackson also studied oral dexamethasone and its relationship to

postoperative pain. Fifty patients were selected that had no signs of swelling or a

draining sinus tract. There were no exclusions based on pulpal status or preoperative

pain. Endodontic debridement was completed, and the patients received either 5.25 mg dexamethasone or placebo divided evenly among 7 tablets. They were instructed to take

the medication or placebo every 3 hours other than while sleeping. Patients were advised

not to take any additional pain medication. Patients were called as close to 8 and 24

hours posttreatment as possible and asked to rate their pain. They found that oral

dexamethasone resulted in significantly less pain in the first 8-24 hours after endodontic

treatment. No differentiation in pulpal diagnosis was made (74).

Liesinger et al. studied the use of variable dosage of intramuscular dexamethasone in patients who had pretreatment tooth pain. One hundred six patients that were diagnosed with irreversible pulpitis with symptomatic apical periodontitis were included.

Treatment was done in either 1 or 2 appointments depending on the appointment time available. At the end of the appointment, patients received 2 mg/ml, 4 mg/ml, 6 mg/ml, or

8 mg/ml of dexamethasone or .9% sterile saline. Patients were asked to rate their pain

(on a 0-9 scale), 1 hour before treatment, during treatment, and 4, 8, 24, 28, 72 hours posttreatment. Patients receiving 2, 4, 6, or 8 mg of dexamethasone had significantly less severe pain at 4 and 8 hours posttreatment, but there was no significant different at hours 45

24, 48, or 72. When comparing these different doses of dexamethasone, patients who received .07-.09 mg/kg had significantly less severe pain at 8 hours than those who received the placebo. Patients who received dexamethasone took a mean of 1.98 pain tablets versus a mean of 4.64 pain tablets for patients receiving the placebo. There was no significant difference in pretreatment pain when comparing the dexamethasone and placebo groups (78).

Mehrvarzfar et al. studied the use of supraperiosteal injection of dexamethasone on postoperative pain. All 100 patients in the study presented with moderate to severe pain from a tooth diagnosed with symptomatic irreversible pulpitis. Endodontic debridement was completed by 2 different operators, and patients received a local injection of 4 mg dexamethasone or 2% lidocaine as a placebo. Patients were asked to record their pain at 6, 12, 24, and 48 hours after the appointment. The results showed that pain was reduced significantly up to 24 hours with the dexamethasone, but no difference was seen at 48 hours. Gender, age, and tooth location did not have any significant difference between the two groups. (69).

Negm studied the combination of a corticosteroid-antibiotic combination when used as an intracanal medicament in vital teeth (4). Nine hundred eighty-eight patients were treated in 3 appointments. Patients were divided into two groups; group 1,

Kenacomb (Bristol-Myers Squibb Company, Cairo, Egypt) which contained nystatin

(100,000 units), neomycin (2.5mg), gramicidin (0.25 mg), and triamcinolone acetonide

(1.0 mg), or group 2, placebo. At the end of the appointment, patients were instructed to rate their pain at 1, 2, 4, 8, 12 and 24 hours postoperatively. If after 24 hours, patients still 46

reported pain, the canal was re-medicated with the same medication. Negm et al. found that the glucocorticoid-antibiotic cream was significantly better than the placebo in controlling posttreatment pain (4).

Another study by Goldberg et al. studied oral dexamethasone in patients with symptomatic irreversible pulpitis. Only 6 patients were included in the study, so they were unable to evaluate the data statistically (83).

In addition to conventional endodontic therapy, steroids have been studied in dentistry to reduce pain following endodontic surgery and oral surgery. Kan et al. (71)

and Lin et al. both studied the use of dexamethasone as a pain reducing agent following

periapical endodontic surgery. Kan et al. studied the use of a 4 mg dexamethasone

submucosal injection following periapical surgery in 60 patients. Patients were divided

into 2 groups; a single local submucosal injection of 4 mg dexamethasone, and a placebo

submucosal injection of saline at the conclusion of a periapical microsurgery.

Acetaminophen and hydrocodone/acetaminophen were prescribed and a Likert-like 6 point scale was completed by the patients. Patients rated pain, bruising, swelling, and wound healing at 24, 28, 72, 96 hours, and at 1 week. The authors found there was no difference in pain, bruising, or wound healing in comparison to a saline placebo at any time. Also, there was no difference in the number of pain pills taken between the two groups. The dexamethasone group showed significant improvement for swelling in the first 24 hours, but there was no benefit for the time periods following. (71). Lin et al. compared the use of 8 mg oral dexamethasone preoperatively followed by two single doses of 4 mg the following two post op days. This group was compared to a placebo 47

group and an etodolac group, an NSAID, given 600 mg preoperatively and 600 mg for

two days postoperatively. Ninety patients were included who needed periapical

microsurgery. Pain was recorded at 8, 24, 48 hours and 1 week postoperatively. The

authors concluded that both dexamethasone and etodolac were effective in reducing

postoperative pain following endodontic surgery compared to the placebo regardless of

the postoperative time. No significant difference was seen between the etodolac group

and the dexamethasone group (75).

Glucocorticoids and Oral Surgery

Glucocorticoids have been studied extensively in an oral surgery model following third molar extraction. Chen et al. conducted a systematic review and meta-analysis of

the effect of submucosal dexamethasone on edema, trismus, and pain following third

molar extraction (67). Eleven studies were used. Patients who received dexamethasone

had significantly less edema and less trismus. Due to multiple methods of pain recording

in the studies, the authors were unable to do a meta-analysis of pain reduction. Four of

the 11 studies reported a nonsignificant decrease in pain after dexamethasone use. Six of

the studies found that dexamethasone could decrease pain following third molar surgery

when compared to a placebo. In regard to pain medication use, 1 study found that analgesic use was more in a control group compared to the dexamethasone group and 2 studies reported that analgesic use was the same regardless of the group.

Schmelzeisen et al. conducted a placebo-controlled double blind study to evaluate postoperative pain and swelling following surgical extraction of third molars. Six mg of

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oral dexamethasone was given 12 hours prior to surgery and 12 hours after surgery of

two impacted molars. Forty volunteers took part in the study. Two operations were

conducted on each patient, and they served as their own control. At the first appointment,

2 teeth were surgically extracted and patients were given either a placebo or the

dexamethasone. Six weeks later, the 2 teeth on the opposite side were removed with the

opposite medication administered. Pain, swelling, and medication use was recorded on a

10 cm VAS. Only 25 patients completed the study. The authors concluded that a 6 mg dose of oral dexamethasone 12 hours before and 12 hours after third molar extraction significantly reduced pain by 50% and the number of analgesics needed by 37% compared to the placebo. Furthermore, 76% of the patients preferred perioperative medication of the dexamethasone compared to the placebo (64).

Baxendale et al. studied the effect of a single preoperative oral dose of 8 mg dexamethasone. Forty-nine patients participated. Two hours prior to third molar extraction, patients were given either 8 mg of dexamethasone or a placebo. Patients then recorded their pain levels immediately after treatment, 4 hours after treatment, and approximately 16 hours after treatment. Postoperative analgesia was administered by nursing staff. If pain was severe, 10 mg of morphine was injected intramuscularly. Two aspirin tablets were given for mild or moderate pain. The authors concluded that a single

8 mg oral dose of dexamethasone preoperatively resulted in a significant reduction in pain 4 hours postoperatively and eliminated the need for opioid analgesia in the postoperative period following third molar surgery. (66)

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Pedersen studied the use of 4 mg of intramuscular dexamethasone following third

molar extraction. Thirty healthy individuals were used that needed identical third molar

extractions on both sides. Patients served as their own control. At the first sitting,

patients were given either a placebo or dexamethasone injection into the masseter, and at

the second sitting patients were given the opposite medication. Pain was evaluated at 2

days and 7 days following the extraction. Pedersen concluded that 4 mg of intramuscular

dexamethasone led to 50% reduction of postoperative swelling and trismus and 30%

reduction of postoperative pain following third molar extraction. (65).

Darwade et al. compared the use of dexamethasone 8 mg vs methylprednisolone

40 mg on swelling, trismus, and pain. Twenty-five patients were included and they acted

as their own control. One hour prior to the procedure, patients were either given 40 mg

methylprednisolone or 8 mg of dexamethasone. At the second sitting, the patients were

given the opposite medication. Pain was assessed at 8 hour intervals for the first three

days and the number of analgesics used was recorded for 7 days. Swelling was also evaluated immediately after treatment and 1, 2, 3, and 7 days after treatment. They concluded a significant reduction in swelling and trismus was found with dexamethasone compared to methylprednisolone. However, no statistically significant difference was

found in postoperative pain between the two medications. (61)

Alcantara et al. did a similar study, but with only 16 patients. The study design and medication amounts were the same as Darwade et al (61). Swelling was evaluated at

1, 2, 3, and 7 days following third molar extraction. Pain was recorded on a VAS at 8 hour intervals for the first 72 hours following third molar extraction. Similar to Darwade 50

et al., the authors found no statistically significant difference between 8 mg of

dexamethasone and 40 mg methylprednisolone with regard to pain, but dexamethasone

controlled swelling better than methylprednisolone at all postoperative time periods.

(62).

Christensen et al. studied a combination of local anesthesia and use of

methylprednisolone and its effect on postoperative pain control following third molar

extraction on 126 patients. Patients were split into 4 groups: Group 1: first appointment:

lidocaine and placebo, second appointment: bupivacaine and methylprednisolone; Group

2: first appointment: bupivacaine and methylprednisolone, second appointment: lidocaine

and placebo; Group 3: first appointment: lidocaine and methylprednisolone, second

appointment: bupivacaine and placebo; Group 4: first appointment: bupivacaine and

placebo, second appointment: lidocaine and methylprednisolone. Patients recorded their

pain levels for the first 2, 4, 6, 8, and 12 hours after surgery and throughout the first 7

postoperative days. Use of methylprednisolone resulted in less pain 4-12 hours after surgery, and for the first 2 days after surgery. Methylprednisolone use also resulted in less swelling at 6 and 12 hours and 1-3 days following surgery. The authors concluded that bupivacaine combined with oral methylprednisolone reduced the postoperative pain and swelling compared with the use of lidocaine and oral placebo, lidocaine and oral methylprednisolone, or bupivacaine and oral placebo. (63)

Ngeow and Lim did a review of articles published from 2005-2015 that studied corticosteroids and their use following third molar surgery. Thirty-four articles were included. Sixteen of the studies showed that corticosteroid use resulted in significant 51

reduction of pain following third molar removal. Twenty-two out of 29 reported a reduction in swelling. Fourteen of the studies showed a reduction of pain, swelling, and trismus. Seventy-one point four percent of these studies used methylprednisolone. The results show that there are benefits for short-term use of corticosteroids in relation to pain following surgical extraction of third molars. (84)

Disease State

The majority of studies discussed above show that the administration of the steroid can improve postoperative pain after conventional endodontic therapy in vital teeth and following endodontic surgery and third molar surgery. However, the administration of a steroid to reduce postoperative pain for teeth with a necrotic pulp has not been studied extensively, and the majority confirms our results that some pain reduction was achieved using a steroid, but it may not be significant. The main difference between teeth diagnosed with pulpal necrosis and teeth diagnosed with irreversible pulpitis is the presence of bacteria and bacterial byproducts and to some extent viruses, fungi, and archea in the canal and the surrounding periapical areas. When a tooth with pulpal necrosis is debrided, the source of the infection is removed. However the bacteria biofilm and bacterial byproducts are still present outside of the tooth in the periapical tissue. We rely on the body to further resolve the infection. Therefore the disease state is much different in comparison to studies of root canal therapy of vital teeth, endodontic surgery, and uncomplicated removal of third molars. The disease states of the above procedures have a minor bacterial component and if there is a bacterial component, it is eliminated during the procedure. In a vital root canal, the source of pain 52

is the pulp tissue within the root canal space. By removing the pulp, the source of the pain is eliminated. While inflammation is present in the periapical tissues, it is not to the same level as a symptomatic tooth diagnosed with pulpal necrosis. In addition, the bacteria and bacterial byproducts that may be present in the vital tissues have not penetrated into the periapical tissues. During endodontic surgery, the inflammation, bacteria, and bacterial byproducts may be in the periapical area, but by accessing the area and removing the inflamed tissue, the majority of the bacteria, and bacterial byproducts are also eliminated. During uncomplicated third molar surgery, there are very little bacterial components involved. Typically there is no pathosis at all, and removal of the third molars is preventative. The main source of pain from third molar surgery is inflammatory in nature. Based on this, it is evident that the source of pain from a symptomatic tooth diagnosed with pulpal necrosis is a different process than pain from a vital tooth, pain from endodontic surgery, and pain from uncomplicated third molar surgery.

Perhaps, the reason the steroid does not significantly reduce pain in symptomatic teeth diagnosed with pulpal necrosis is the disease state. Different bacterial species dominate at different levels of the root canal. Changes in the microbiota are due to changes in the environmental conditions including oxygen availability and nutrient availability. After a few days or weeks oxygen is depleted with the root canal as a result of necrosis. An anaerobic environment develops and is highly conducive to the survival and growth of obligate anaerobic bacteria. With the passage of time, anaerobic conditions become more pronounced, particularly in the apical third of the root

53

canal. The main source of nutrients for bacteria are necrotic tissue, proteins and

glycoproteins from tissue fluids and exudate that seep into canals via the foramen,

components of saliva, and products of the metabolism of other bacteria (49).

Gomes et al. found an association between specific bacteria and the presence of pain. The bacteria most associated with endodontic pain are Prevotella and

Peptostreptococcus species (85). In a later article, the same authors reached the same conclusion including the specific bacteria Peptostreptococcus micros and Prevotella melaninogenicia as pain causing bacteria in periapical infections (86).

If bacteria and infection are the main source of pain in teeth diagnosed with pulpal necrosis, then an antibiotic should be sufficient at reducing the pain. However, Henry et al. (39), Cope et al. (40), and Veitz-Keenan et al (87). found evidence to refute this.

Cope et al. conducted a systematic Cochrane review article. The review agreed with

Henry et al,. as discussed earlier, that there was no pain reduction from the use of

antibiotics compared to a placebo for symptomatic teeth diagnosed with pulpal necrosis,

but further studies need to be completed because the evidence is limited (40). Perhaps

the combination of inflammation and infection is too strong of a process to overcome

with the use of a steroid.

What about virally mediated pain? Viruses have been shown to play a component

in pain from periapical periodontitis (88, 89, 90, 91). Hernandez et al. completed a

review of multiple articles and found that Cytomegalovirus and Epstein-Barr virus were

both present in a significant number of endodontic-originated periapical periodontitis

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(88). Jakovljevic et al. completed a similar review and found that Herpes virus were

prevalent in symptomatic periapical lesions, and large periapical lesions (89). Slots et al.

conducted a study to compare the presence of Cytomegalovirus and Epstein-Barr virus in periapical lesions. The authors found that Cytomegalovirus was overwhelmingly present in symptomatic periapical lesions. Epstein-Barr virus was also present in symptomatic periapical lesions, but to a lesser extent than Cytomegalovirus (90). Similarly, Sabeti et al. concluded that both Cytomegalovirus and Epstein-Barr virus infections are associated

with acute pain from periapical periodontitis (91). Virally mediated pain in endodontics

needs to be studied further, but there appears to be some evidence that viruses play a role

in causing pain in periapical periodontitis. If viruses play a role in causing pain, perhaps

an antiviral medication will be effective in controlling pain in symptomatic teeth

diagnosed with pulpal necrosis. To our knowledge, no studies on this topic have been

conducted.

The disease state associated with a symptomatic tooth diagnosed with pulpal

necrosis is very dynamic. The disease state as it relates to pain should be investigated

further. Based on our study, the disease state of a symptomatic tooth with pulpal necrosis

is hard to overcome with a high dose of methylprednisolone giving us reason to believe

the bacteria and viruses may play a component in pain from periapical periodontitis.

The current analgesic regimen given by most endodontists is acetaminophen,

NSAIDs, narcotics, or a combination of these. In our study, the comparison of a high

dose steroid to a placebo shows that pain reduction among symptomatic teeth diagnosed

with pulpal necrosis is not an appropriate medication regimen to reduce postoperative 55

pain. While pain was reduced between the groups, the risks of side effects compared to

the placebo are potentially much greater with little benefit to justify its use. To warrant its

use, we would want to see a highly significant reduction in pain when compared to a

placebo. If there was a highly significant result comparing the placebo to the steroid the

next step would be to compare the same high dose steroid to a widely accepted

postoperative analgesic course such as 600 mg ibuprofen or 650 mg acetaminophen.

However, if this study was conducted, we expect the difference to be even less than what

we currently observed. Most likely this would show compelling evidence that a high

dose of methylprednisolone is not a useful adjunct to reducing postoperative pain in

comparison to the widely accepted analgesic regimens. This is especially important

when considering the increased risk of adverse events with increased doses of a drug. In

other words, one would want to use the lowest dose of a drug that would still maintain

effectiveness.

Swelling

Table 7 shows swelling status of patients by group for each day following

endodontic treatment. Rather than a direct measure of swelling, this was more of a

subjective measure on how the patients were feeling each day. In our study, no patients

needed to return to the clinic for evaluation of swelling or administration of a

postoperative antibiotic course. There was no significant difference between the groups

with regard to swelling status being better, worse, or the same. This data can be a little

misleading because the number of patients reporting their swelling as better decreased as

the days went on. Most patients reported that their swelling was better, and if it did not 56

worsen, they reported their swelling as being the same for the remainder of the surveyed days. With this in mind, I will discuss the number of patient’s reporting that their swelling became worse throughout the surveyed days. Regardless of the group, patients’ swelling improved. On days 4-7, only four patients in both groups reported their swelling being worse. Only 17 patients on any surveyed day experienced worsening swelling. At the beginning of treatment only two patients who were enrolled had visible mild swelling.

Both of these patients were randomly assigned to the placebo group and both swellings were localized on the palatal tissue.

Some people feel that administering a steroid while an active infection is present could lead to more serious complications. No patients in the study had adverse events, as it relates to a spreading infection, with the use of a corticosteroid in the presence of apical periodontitis. Youssef et al. conducted a review, and studied the effects of long term corticosteroid use and risk of infection due to the immunosuppressive actions of steroids.

They found that while infection risk has been well documented, the short term and lower dose steroids have not shown any increased risk of infection. In addition, observational studies have shown a risk for opportunistic infections i.e. herpes zoster, tuberculosis, and pneumocystis pneumonia (92). The bacteria that have been implicated in symptomatic apical periodontitis, as discussed earlier, pose a low risk for spread of infection. That, in combination with the short term course of a steroid, poses very low risk for systemic infection. All patients who were enrolled in our study were healthy individuals with low risk of co-morbidities, having no to mild swelling.

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In a comparative study, Claffey and co-authors reported that subjects in the placebo group had a significant increase in swelling on days 1-3 compared to the steroid medication group. The authors hypothesized that the steroid was able to significantly reduce swelling due to the inflammatory reduction within the bone (10). These results are different than what we found. We categorized swelling without a measurement and only on a better, same, worse scale compared to Claffey and co-authors giving the swelling a numeric score and comparing daily results. Furthermore, swelling is a highly subjective measure making the variation among the patients hard to control. With the idea in mind that this is a measure of how they are feeling instead of true swelling, it can be observed that regardless of the group, most patients felt better by day 7.

Analgesic and Escape Drug Use

Tables 8a, 8b, and 9 illustrate the number of patients needing any analgesic medication (600 mg Ibuprofen or Tylenol #3) (Table 8), patients needing only ibuprofen

(Table 9), and the number of patients needing the escape drug (Tylenol #3) (Table 10).

Tables 8a shows that on day 2 and day 3 patients in the steroid group took significantly less analgesic medication compared with the placebo group. This is likely due to the gender differences. Males in the steroid group took significantly more analgesic medications than males in the placebo group on day 2 (p = 0.0463) and on day 3 (p =

0.0268). The males’ showed significance, but the females did not. When a comparing the numbers on day 2, females in the placebo group took 1.9 tablets while males in the placebo group took 2.5 tablets. On day 3, females in the placebo group took 1.4 tablets and males took 3.1 tablets. Even though it does show statistical significance, the 58

difference between the males and females on day 2 is half a tablet and on day 3

approximately one and a half tablets. This is not clinically significant. Day 4 approached

statistical significance with 10% of patients in the placebo group needing analgesic

medication. On days 2 and 3, patients in the placebo group needed approximately 2

tablets while patients in the steroid group needed less than 1, on average. By day 5,

patients in both groups needed less than 1 analgesic tablet per day, and continued to

decrease throughout the surveyed time period. Table 9, shows very similar results in that

patients in the steroid group took significantly less ibuprofen on days 2 and 3, and by day

5 the groups were essentially equal (p=1.0000). By day 4, both groups needed less than 1

ibuprofen tablet.

This data is supported by the study done by Claffey et al. in that study patients

took significantly less pain medication on day 1 and day 2, but not on day 3 or the

remainder of the evaluation days. While our patients took less medication on day 1, it

was not statistically significant. Our patients took significantly less medication on day 3,

while Claffey and co-authors showed no significance at day 3. This is most likely

explained by a lower methylprednisolone dose that was given in their study. Another

explanation for this difference could be that Claffey et al. did not have as large of a

sample size as this study. Only thirty-four patients were evaluated and 10 of these patient’s data were obtained from another study. Even with this in mind, the amount of analgesics that were taken was very small. While it is statistically significant on days 2 and 3, the clinical significance can be debated. The difference between the two groups on days 2 and 3 was essentially 1 tablet. The small difference, while statically

59

significant, would not warrant a change in clinical protocol to a high-dose steroid to help control postoperative pain. In order to warrant a change in clinical protocol, we would want to see a much larger difference between the two groups.

The total analgesic use agrees with previous studies evaluating symptomatic necrotic teeth. Wells et al., Sebastian et al., and Glenn et al. all showed the highest analgesic use occurring on postoperative day 1 followed by a gradual decline throughout the surveyed days (1, 2, 46). All of the above mentioned studies only surveyed patients for 5 postoperative days. In our study, it was shown that analgesic use continued to decline on postoperative days 6 and 7.

With regard to narcotic use, Table 10 displays the percentage of patients, by group, that needed the escape medication. The total number of patients who needed the escape medication was 23% for the steroid group and 37% for the placebo group. There was no statistical difference. On day 2, narcotic use was at its highest and remained near peak levels on day 3. Following day 3, narcotic use decreased.

Claffey et al. found similar results with regard to narcotic use. Patients used significantly more narcotic analgesics on the first three days in the study group when compared to the placebo group. Following day 3, narcotic use declined in the placebo group, but in the steroid group narcotic use increased following day 3 (10). As discussed earlier, this was hypothesized to be from a rebound effect of the inflammatory process.

In our study, we did not see an increase in narcotic analgesic use once the steroid

60

medication was discontinued at day 5. Either increasing the dose of methylprednisolone

or its duration of use appears to have eliminated this rebound effect.

Wells et al. reported similar findings that days 1-3 had the highest narcotic analgesic use (46). Sebastian et al. found that the highest need for narcotic analgesic medication occurred on days 1 and 2 (1). Glenn et al. found that overall 18% of patients utilized a narcotic analgesic with the highest use occurring on posttreatment days 2-4 (2).

Analgesic use on days 2 and 3 were the only statistically significant differences

found in our study between groups (p<0.0181 and 0.0147). As mentioned earlier, these

values are statistically significant, but the difference was only 1 tablet per day. We

compared the high dose methylprednisolone to a placebo, but what if we compared the

high dose methylprednisolone to a normal analgesic regimen (600 mg Ibuprofen)?

Methylprednisolone had inconsequential effect on analgesic use when compared to

placebo. Therefore, if we compared the same dose methylprednisolone to a current

analgesic regimen the effect of the methylprednisolone would be further minimized. This

was discussed earlier when relating the methylprednisolone to pain reduction. Likely we

would see an even smaller difference between the groups and may eliminate the

significance between the two groups on day 2 and day 3.

Success

Table 11 and 12 illustrate success by day and the fixed effects related to success.

Success was defined as no to mild pain as marked on the 170 mm VAS, and the

avoidance of narcotic pain medication. No to mild pain has been used as a definition of

61

success by previous authors (2, 10). If a patient experiences no to mild pain, it can likely

be controlled with the use of ibuprofen alone or other non-narcotic medications (2, 10,

46). However, if a patient is experiencing moderate to severe pain they are more likely to

take narcotic analgesic medications. In an attempt to have a direct comparison to other

studies, the definition of success was maintained the same as previous authors conducting similar studies.

If we can control pain to none to a level of mild, avoidance of a narcotic medications can be achieved. Narcotic pain medications carry many side effects.

Addiction to narcotic pain medications has become a very prevalent issue in today’s society. It is estimated that over 2.1 million Americans suffer from opioid addiction from prescription pain medications (93). It is thought that this number is increasing due to the increase in prescriptions written for narcotic pain medications. From 1991 to 2012, the number of prescriptions written has almost tripled to 210 million per year (93). A current effort by the state of Ohio has aimed to limit the number of narcotic medications prescribed. The new legislation has enacted limits on the morphine equivalents, created prescription drug monitoring software (OARRS), and a limit on what medications can be prescribed by phone. These legislative measures and general awareness have resulted in

a decrease of narcotic prescriptions written by almost 18% from 2012 to 2015 (94). There

is more legislation that may further limit our ability to prescribe narcotic pain medication

in the future. With this in mind, it is essential to find a means to help control pain levels

without the use of the habit-forming narcotic analgesics.

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When success was defined as described above, there was no statistically significant difference between the placebo and steroid groups. Although not significant, the steroid group had higher success on days 1, 2, 3, and 4. On day 1, the placebo group had success of only 57% while the steroid group had success of 68%. By day 6, both groups had success rates that were over 90%. Table 12 shows that the group was not significant in predicting success, but the postoperative day was highly significant. As you can see in Figure 4, as the number of days increased the likelihood of success increased. Finally, when the interaction of group by day was analyzed, it was not significant.

Claffey and coauthors found similar success rates, compared to our study, on days

1-3 with the steroid group. However their success with the steroid group declined following day 3 for reasons discussed earlier. Similar success rates were described for the placebo groups with success increasing each day of the postoperative period (10).

Glenn et al. defined success the same as we have, but success was not broken down by day. The overall success was lower than what we have reported suggesting that the bupivacaine was not as efficacious at reducing moderate to severe pain.

We found that administration of a steroid had no significant difference in success following endodontic treatment of a symptomatic tooth diagnosed with pulpal necrosis.

Regardless of the group, the success increased each postoperative day. For reasons discussed earlier in the postoperative pain section, it can be concluded that the administration of the steroid did not reduce pain and narcotic use enough to warrant its routine use at such a high dose for symptomatic teeth diagnosed with pulpal necrosis. If 63

the high dose was effective, then follow up studies could determine if lower doses would be effective.

64

Chapter 5: Summary and Conclusions

This study evaluated whether a high dose of methylprednisolone would help to

reduce postoperative pain in symptomatic teeth diagnosed with pulpal necrosis. We can

conclude while pain was reduced in the steroid group, it was not statistically or clinically

significant.

Furthermore, the total analgesic use showed a statistically significant difference

between the steroid and placebo groups. However this was not clinically significant

because it was only a difference of 1 tablet per day.

Success as defined as mild pain or less and no narcotic use, showed no statistical

difference between the two groups. Regardless of the group, success increased by day,

and by day 7 success was greater than 90% for both groups.

Methylprednisolone is a potent anti-inflammatory, and when used at the dose used in the current study, we would expect to see a reduction of pain and analgesic use.

However, pain from a symptomatic tooth diagnosed with pulpal necrosis has a disease state that is much more than inflammatory pain. The disease process may be too advanced that the steroid cannot have an adequate effect, or the bacteria, bacterial byproducts, viruses, and other unknown factors play a major role in pain perception.

65

The difference between the placebo and the steroid group does not warrant a follow-up study to compare the same dose of methylprednisolone to a common anti- inflammatory regimen such as ibuprofen. The potential side effects of a high dose steroid outweigh the benefits of a small reduction in pain or small reduction in analgesic medication taken. Future studies need to be conducted to find a way to control postoperative pain of a symptomatic tooth diagnosed with pulpal necrosis because a high dose of methylprednisolone was not shown to be a beneficial solution.

66

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Appendix A Tables

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Table 1

Evaluation of Initial Pain, Age, Weight, and Antibiotic Use

Initial Initial Age Age Weight Weight Pre-Op Pain Pain Mean ± Median Mean ± SD Median Antibiotics Mean ± Median SD (years) (years) (lbs) (lbs.) (% Yes) SD (mm) (mm) Placebo 135±20 134 33 ±14 28 172 ± 48 168 12 (10/82) Steroid 129 ± 23 131 36 ± 13 32 183 ± 50 170 17 (14/82) P Value 0.2268* 0.3786* 0.2960* 0.3316** *Randomization test

**Chi Square

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Table 2

Breakdown of Gender Between Groups

# of Subjects Male Female Total 39% 61%

(32/83) (51/83)

Placebo 33% 67% (14/42) (28/42) Steroid 44% 56% (18/41) (23/41) *P Value 0.3226

*Chi Square

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Table 3

Preoperative Analgesic Use

None NSAIDs Acetaminophen Narcotic NSAID + Tylenol Placebo 58% 32% 5% 5% 0 (22/38) (12/38) (2/38) (2/38) (0/38) Steroid 43% 27% 11% 14% 5% (2/37) (16/37) (10/37) (4/37) (5/37) *P 0.4605 Value *Fisher Exact Test

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Table 4

Injection Pain

Group Jaw Injection Injection Injection Insertion Placement Deposition Mean ± SD Mean ± SD Mean ± SD {median} (mm) {median} (mm) {median} (mm) Placebo* Maxillary 43 ± 43 {23} 52 ± 42 {39} 69 ± 55 {61} Mandibular 35 ± 36 {25} 51 ± 41 {51} 53 ± 42 {56} Steroid* Maxillary 39 ± 29 {38} 49 ± 46 {38} 61 ± 52 {49} Mandibular 45 ± 39 {38} 59 ± 47 {45} 63 ± 43 {61} *Randomization test and step-down Bonferroni method of Holm (P values = 1.0000 for Insertion, Placement, and Deposition)

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Table 5 Treatment Pain

Dentin Pulp Chamber Instrumentation

Mean ± SD Mean ± SD Mean ± SD {median} {median}(mm) {median} (mm) (mm)

Placebo 6 ± 15 {0} 7 ± 15 {0} 25 ± 28 {21}

None 64% 52% 26%

Mild 33% 45% 52%

Moderate 3% 3% 22%

Severe 0 0 0

Steroid 5 ± 10 {0} 13 ± 25 {0} 23 ± 24 {18}

None 56% 54% 27%

Mild 44% 39% 56%

Moderate 0 7% 17%

Severe 0 0 0

*P Value 1.0000 0.7196 1.0000

* Randomization test and step-down Bonferroni method of Holm

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Table 6 Percentages and Discomfort Ratings of Steroid and Placebo Groups Day Group None Mild Moderate Severe Mean ± SD *P (mm) Value 1 Placebo 5% 55% 36% 5% 55 ± 37 0.0969 (2/42) (23/42) (15/42) (2/42) Steroid 18% 53% 28% 3% 34 ± 38 (7/40) (21/40) (11/40) (1/40) 2 Placebo 12% 57% 31% 0 38 ± 32 1.0000 (5/42) (24/42) (13/42) (0/42) Steroid 29% 41% 27% 2% 31 ± 36 (12/41) (17/41) (11/41) (1/41) 3 Placebo 21% 57% 21% 0 28 ± 29 0.4191 (9/42) (24/42) (9/42) (0/42) Steroid 34% 54% 12% 0 18 ± 22 (14/41) (22/41) (5/41) (0/41) 4 Placebo 38% 50% 10% 2% 20 ± 27 0.7580 (16/42) (21/42) (4/42) (1/42) Steroid 48% 43% 10% 0 12 ± 20 (19/40) (17/40) (4/40) (0/40) 5 Placebo 52% 43% 5% 0 12 ± 19 1.0000 (22/42) (18/42) (2/42) (0/42) Steroid 60% 30% 10% 0 14 ± 24 (24/40) (12/40) (4/40) (0/40) 6 Placebo 57% 40% 2% 0 8 ± 16 1.0000 (24/42) (17/42) (1/42) (0/42) Steroid 63% 38% 0 0 8 ± 14 (25/40) (15/40) (0/40) (0/40) 7 Placebo 69% 29% 2% 0 6 ± 14 1.0000 (29/42) (12/42) (1/42) (0/42) Steroid 73% 25% 3% 0 5 ±11 (29/40) (10/40) (1/40) (0/40) * Randomization test and step-down Bonferroni method of Holm

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Table 7

Swelling Status

Day Group Better Worse Same Median *P Value ± IQR 1 Placebo 49% (18/37) 11% (4/37) 41% (15/37) 1 ± 1 0.4358 Steroid 68% (26/38) 3% (1/38) 29% (11/38) 2 ± 1 2 Placebo 53% (19/36) 6% (2/36) 42% (15/36) 2 ± 1 1.0000 Steroid 58% (23/40) 10% (4/40) 33% (13/40) 2 ± 1 3 Placebo 68% (25/37) 3% (1/37) 30% (11/37) 2 ± 1 1.0000 Steroid 74% (29/39) 3% (1/39) 23% (9/39) 2 ± 1 4 Placebo 77% (27/35) 0 (0/35) 23% (8/35) 2 ± 0 1.0000 Steroid 71% (27/38) 0 (0/38) 29% (11/38) 2 ± 1 5 Placebo 71% (25/35) 3% (1/35) 26% (9/35) 2 ± 1 1.0000 Steroid 61% (23/38) 3% (1/38) 37% (14/38) 2 ± 1 6 Placebo 63% (2/32) 0 (0/32) 38% (12/32) 2 ±1 1.0000 Steroid 51% (19/37) 3% (1/37) 46% (17/37) 2 ± 1 7 Placebo 66% (21/32) 0 (0/32) 34% (11/32) 2 ± 1 1.0000 Steroid 50% (19/38) 3% (1/38) 47% (18/38) 1.5 ± 1 *Mann-Whitney Wilcoxon test and step-down Bonferroni method of Holm

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Table 8 Mean Number of Analgesic Tablets Utilized by Day

Day Group % Analgesic Number of Tabs *P Value Use Mean ± SD 1 Placebo 60% (25/42) 1.3 ± 1.7 0.4100 Steroid 44% (18/41) 0.7 ± 1.1 2 Placebo 71% (30/42) 2.1 ± 2.1 0.0181 Steroid 49% (20/41) 0.9 ± 1.2 3 Placebo 52% (22/42) 2.0 ± 2.6 0.0147 Steroid 35% (14/40) 0.7 ± 1.0 4 Placebo 38% (16/42) 1.2 ± 1.9 0.0777 Steroid 28% (11/40) 0.4 ± 0.8 5 Placebo 27% (11/41) 0.8 ± 1.4 0.6741 Steroid 25% (10/40) 0.5 ± 0.9 6 Placebo 22% (9/41) 0.5 ± 1.0 1.0000 Steroid 18% (7/40) 0.3 ± 0.8 7 Placebo 7% (3/41) 0.1 ± 0.6 1.0000 Steroid 10% (4/40) 0.2 ± 0.6 *Randomization Test with Step-down Bonferroni method of Holm

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Table 9

Mean Number of Ibuprofen Tablets Utilized by Day

Day Group % Ibuprofen Number of Tabs *P Value Mean ± SD 1 Placebo 55% (23/42) 1.0 ± 1.3 0.3865 Steroid 44% (18/41) 0.6 ± 0.8 2 Placebo 71% (30/42) 1.8 ± 1.6 0.0055 Steroid 41% (17/41) 0.7 ± 1.0 3 Placebo 52% (22/42) 1.4 ± 1.7 0.0209 Steroid 29% (12/41) 0.5 ± 0.9 4 Placebo 34% (14/41) 0.8 ± 1.2 0.3865 Steroid 27% (11/41) 0.4 ± 0.7 5 Placebo 22% (9/41) 0.5 ± 1.0 1.0000 Steroid 23% (9/40) 0.3 ± 0.7 6 Placebo 17% (7/41) 0.3 ± .08 1.0000 Steroid 15% (6/40) 0.3 ± 0.7 7 Placebo 5% (2/40) 0.1 ± 0.5 1.0000 Steroid 8% (3/40) 0.1 ± 0.5 *Step-down Bonferroni method of Holm

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Table 10

Escape Drug Use by Day

Day Group % Success

1 Placebo 12% (5/42) Steroid 10% (4/41)

2 Placebo 21% (9/42) Steroid 17% (7/41)

3 Placebo 21% (9/42) Steroid 15% (6/41) 4 Placebo 20% (8/41) Steroid 7% (3/41) 5 Placebo 15% (6/41)

Steroid 7% (3/41) 6 Placebo 7% (3/41) Steroid 5% (2/41) 7 Placebo 3% (1/40) Steroid 5% (2/41)

Odds Ratio 0.577 95% Confidence 0.304-1.096 Interval

P Value 0.0930 *Logistic Regression

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Table 11

Success by Day Day Group % Success 1 Placebo 57% (24/42) Steroid 68% (28/41) 2 Placebo 64% (27/42) Steroid 66% (27/41) 3

Placebo 69% (29/42) Steroid 76% (31/41) 4

Placebo 76% (32/41) Steroid 88% (36/41) 5 Placebo 83% (35/41) Steroid 85% (35/40) 6 Placebo 90% (38/41) Steroid 95% (39/40)

7 Placebo 95% (39/40) Steroid 93% (38/40)

Odds Ratio 0.662 95% 0.401-1.733 Confidence Interval

P Value 0.1064 *Logistic Regression

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Table 12

Type III Tests of Fixed Effects of Success Effect Num DF *P Value Group 1 0.1058 Day 6 <.0001 Group * Day 6 0.9171

*Logistic Regression

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Appendix B Figures

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Figure 1: Postoperative Pain by Group and Day

Postoperative Pain by Group and Day

160.0 140.0 120.0 100.0 80.0 PLACEBO 60.0 40.0 STEROID 20.0 0.0 MEAN MEAN PAIN SCORE (mm) 1 2 3 4 5 6 7 Day

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Figure 2: Total Analgesic Use

Total Analgesic Use 12.0

10.0

8.0

6.0 PLACEBO 4.0 STEROID Number Tablets of 2.0

0.0 1 2 3 4 5 6 7 Day

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Figure 3: Ibuprofen Use by Group and Day

Ibuprofen Use by Group and Day 12.0

10.0

8.0

6.0 PLACEBO

4.0 STEROID Number Tablets of

2.0

0.0 1 2 3 4 5 6 7 Day

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Figure 4: Success by Day

Success by Day 100.0 90.0 80.0 70.0 60.0 50.0 PLACEBO 40.0 % Success STEROID 30.0 20.0 10.0 0.0 1 2 3 4 5 6 7 Day

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Appendix C Initial Pain VAS

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Initial Pain Rating

Date: ______Code #: ______

1. Please mark a vertical line on the line below to rank the level of pain you are feeling today.

None Faint Weak Mild Moderate Strong Intense Maximum Possible

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Appendix D Health History

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Appendix E Consent Form

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The Ohio State University Consent to Participate in Research

Postoperative pain management for necrotic teeth using a steroid Study Title: Principal Investigator: Dr. Melissa Drum D.D.S. M.S.

Sponsor: Not applicable

• This is a consent form for research participation. It contains important information about this study and what to expect if you decide to participate. Please consider the information carefully. Feel free to discuss the study with your friends and family and to ask questions before making your decision whether or not to participate. • Your participation is voluntary. You may refuse to participate in this study. If you decide to take part in the study, you may leave the study at any time. No matter what decision you make, there will be no penalty to you and you will not lose any of your usual benefits. Your decision will not affect your future relationship with The Ohio State University. If you are a student or employee at Ohio State, your decision will not affect your grades or employment status. • You may or may not benefit as a result of participating in this study. Also, as explained below, your participation may result in unintended or harmful effects for you that may be minor or may be serious depending on the nature of the research. • You will be provided with any new information that develops during the study that may affect your decision whether or not to continue to participate. If you decide to participate, you will be asked to sign this form and will receive a copy of the form. You are being asked to consider participating in this study for the reasons explained below.

1. Why is this study being done?

The purpose of this study is to determine if the administration of a steroid ( an anti- inflammatory medication) would help decrease postoperative pain following root canal treatment.

2. How many people will take part in this study? One hundred and twenty people (120) will take part in this study.

3. What will happen if I take part in this study?

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You have a tooth, which is hurting (painful), and you are aware that it needs a root canal. If you decide to participate in this study, you will be required to complete a medical history questionnaire. You will be asked to rate the pain you are having prior to any treatment. You will do this by marking your pain with a pen on a line graph. The tooth causing your pain will first be tested to ensure an accurate diagnosis. It will be tested with a cold cotton pellet chilled with an ice spray. The cold test is used routinely before root canal treatment. Your tooth will also be tested with an electric pulp tester, this is also used routinely before root canal treatment. This may cause a slight, temporary warm sensation to the teeth tested.

Local anesthetic (numbing solution) will then be administered in a routine manner to make your tooth numb. You will rate your pain following the injection. Root canal treatment will be started on your tooth following standard protocols. You will rate your comfort during treatment. As is typical of emergency root canal procedures, the root canal will only be started at this appointment and you will need to return at least one more time to finish the procedure.

At the end of today’s appointment, you will be given either methylprednisolone (a steroid) or a sugar pill. Whether you receive the medication or the sugar pill will be randomly assigned, like the flip of a coin. You will also be given ibuprofen tablets and a prescription for escape drug (narcotic). The purpose of this study is to determine if the steroid decreases pain associated with your tooth compared to the sugar pill.

At the conclusion of your appointment, you will be given medications and a questionnaire to take home. You will be asked to keep a diary to record your pain level and the medication that was taken each day for the next 8 days starting today. If the ibuprofen does not control your pain, an escape medication may be prescribed. You will be asked to take no other pain medications other than those given or prescribed. You will be encouraged to schedule an appointment to finish the root canal treatment.

If you are a female and are pregnant or nursing, you will not be able to participate. If you are a woman able to have children, you may be required to take a urine pregnancy test before participation. The study requires one appointment but you will need at least one additional appointment to finish the root canal.

Your participation or non-participation will have no effect on whether you will receive emergency root canal treatment. You understand that if you want to save the treated tooth (provided it is restorable or savable) further root canal treatment and restorative treatment such as a filling and or a crown will be needed. You will be responsible for the emergency root canal and tooth restoration fee.

If you are a student or staff member at OSU and choose not to participate in this study, your grades and/or employment will not be affected

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4. How long will I be in the study?

You will have one appointment, which will last approximately 120 minutes. You will be required to complete a questionnaire over a 8 day period, including today. You will need to return for at least one more appointment to finish the root canal.

5. Can I stop being in the study?

You may leave the study at any time. If you decide to stop participating in the study, there will be no penalty to you, and you will not lose any benefits to which you are otherwise entitled. Your decision will not affect your future relationship with The Ohio State University.

6. What risks, side effects or discomforts can I expect from being in the study? Use of methylprednisolone (an anti-inflammatory medication), may cause depression, euphoria, insomnia, mood swings, personality disorders, diarrhea, nausea, or bleeding of the stomach. You may have an allergic reaction (rash, difficulty breathing) to ibuprofen, which is very rare, upset stomach, nausea, heartburn, diarrhea, gastric bleeding, and increased bleeding. Both of these medications may be provided during routine root canal therapy

If you are a woman able to have children, you will be questioned regarding pregnancy or suspected pregnancy and will not be allowed to participate if pregnant, suspect a pregnancy, trying to become pregnant, or nursing. Additionally, may be required to take a urine pregnancy test before you can start this study. The reason for excluding pregnant or potentially pregnant women is an attempt to minimize this population in the study because the potential risks to the fetus and nursing baby are unknown.

7. What benefits can I expect from being in the study?

You will not directly benefit from this study but you may have decreased pain following the treatment.

8. What other choices do I have if I do not take part in the study? You may have the emergency root canal procedure completed without participating in the study. You may choose not to participate without penalty or loss of benefits to which you are otherwise entitled.

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9. Will my study-related information be kept confidential?

Efforts will be made to keep your study-related information confidential. However, there may be circumstances where this information must be released. For example, personal information regarding your participation in this study may be disclosed if required by state law.

Also, your records may be reviewed by the following groups (as applicable to the research): • Office for Human Research Protections or other federal, state, or international regulatory agencies; • U.S. Food and Drug Administration; • The Ohio State University Institutional Review Board or Office of Responsible Research Practices; • The sponsor supporting the study, their agents or study monitors; and • Your insurance company (if charges are billed to insurance).

If this study is related to your medical care, your study-related information may be placed in your permanent hospital, clinic, or physician’s office records. Authorized Ohio State University staff not involved in the study may be aware that you are participating in a research study and have access to your information.

A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. law. This website will not include information that can identify you. At most, the website will include a summary of the results. You can search the website at any time.

You may also be asked to sign a separate Health Insurance Portability and Accountability Act (HIPAA) research authorization form if the study involves the use of your protected health information.

10. What are the costs of taking part in this study?

Costs such as parking and future treatment will not be reimbursed in this study. Should you request the escape drug, you will be responsible for the cost incurred. You are responsible for the root canal fee.

11. Will I be paid for taking part in this study? You will receive up to $100 to participate in this study. If you complete the first visit, you will receive $20. You will receive an additional $80 upon completion and return of the 8- day diary and return of all unused study medications. By law, payments to subjects are considered taxable income.

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12. What happens if I am injured because I took part in this study?

If you suffer an injury from participating in this study, you should notify the researcher or study doctor immediately, who will determine if you should obtain medical treatment at The Ohio State University Medical Center.

The cost for this treatment will be billed to you or your medical or hospital insurance. The Ohio State University has no funds set aside for the payment of health care expenses for this study.

13. What are my rights if I take part in this study?

If you choose to participate in the study, you may discontinue participation at any time without penalty or loss of benefits. By signing this form, you do not give up any personal legal rights you may have as a participant in this study.

You will be provided with any new information that develops during the course of the research that may affect your decision whether or not to continue participation in the study.

You may refuse to participate in this study without penalty or loss of benefits to which you are otherwise entitled.

An Institutional Review Board responsible for human subjects research at The Ohio State University reviewed this research project and found it to be acceptable, according to applicable state and federal regulations and University policies designed to protect the rights and welfare of participants in research.

This research project was awarded a grant from the American Association of Endodontists Foundation. This grant helps with the financial cost of conducting the study. The American Association of Endodontists Foundation is not a stakeholder in the design or results of this study.

14. Who can answer my questions about the study?

For questions, concerns, or complaints about the study you may contact Dr. Melissa Drum or Dr. Michael Fuller at 614 – 292-5399

For questions about your rights as a participant in this study or to discuss other study related concerns or complaints with someone who is not part of the research team, you

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may contact Ms. Sandra Meadows in the Office of Responsible Research Practices at 1- 800-678-6251.

If you are injured as a result of participating in this study or for questions about a study- related injury, you may contact Dr. Melissa Drum or Dr. Michael Fuller at 614 – 292- 5399.

Signing the consent form

I have read (or someone has read to me) this form and I am aware that I am being asked to participate in a research study. I have had the opportunity to ask questions and have had them answered to my satisfaction. I voluntarily agree to participate in this study.

I am not giving up any legal rights by signing this form. I will be given a copy of this form.

Printed name of subject Signature of subject

AM/PM Date and time

Printed name of person authorized to consent for Signature of person authorized to consent for subject subject (when applicable) (when applicable)

AM/PM Relationship to the subject Date and time

Investigator/Research Staff

I have explained the research to the participant or his/her representative before requesting the signature(s) above. There are no blanks in this document. A copy of this form has been given to the participant or his/her representative.

Printed name of person obtaining consent Signature of person obtaining consent

AM/PM Date and time

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Witness(es) - May be left blank if not required by the IRB

Printed name of witness Signature of witness

AM/PM Date and time

Printed name of witness Signature of witness

AM/PM Date and time

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Appendix F Privacy Form

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THE OHIO STATE UNIVERSITY AUTHORIZATION TO USE PERSONAL HEALTH INFORMATION IN RESEARCH

Title of the Study: Postoperative pain management for necrotic teeth using a steroid

Protocol Number: 2015H0428

Principal Investigator: Melissa Drum DDS MS

Subject Name______

Before researchers use or share any health information about you as part of this study, The Ohio State University is required to obtain your authorization. This helps explain to you how this information will be used or shared with others involved in the study.

• The Ohio State University and its hospitals, clinics, health-care providers, and researchers are required to protect the privacy of your health information. • You should have received a Notice of Privacy Practices when you received health care services here. If not, let us know and a copy will be given to you. Please carefully review this information. Ask if you have any questions or do not understand any parts of this notice. • If you agree to take part in this study your health information will be used and shared with others involved in this study. Also, any new health information about you that comes from tests or other parts of this study will be shared with those involved in this study. • Health information about you that will be used or shared with others involved in this study may include your research record and any health care records at The Ohio State University. For example, this may include your medical records, x-rays, or laboratory results. Psychotherapy notes in your health records (if any) will not, however, be shared or used. Use of these notes requires a separate, signed authorization.

Please read the information carefully before signing this form. Please ask if you have any questions about this authorization, the university’s Notice of Privacy Practices or the study before signing this form.

Those Who May Use, Share, and Receive Your Information as Part of This Study

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• Researchers and staff at The Ohio State University will use, share, and receive your personal health information for this research study. Authorized Ohio State staff not involved in the study may be aware that you are participating in a research study and have access to your information. If this study is related to your medical care, your study-related information may be placed in your permanent hospital, clinic, or physician’s office records.

Initials/Date: ______Those who oversee the study will have access to your information, including the following: • Members and staff of The Ohio State University’s Institutional Review Boards, including the Western Institutional Review Board • The Ohio State University Office of Responsible Research Practices • University data safety monitoring committees • The Ohio State University Office of Research.

• Your health information may also be shared with federal and state agencies that have oversight of the study or to whom access is required under the law. These may include the following: • Food and Drug Administration • Office for Human Research Protections • National Institutes of Health • Ohio Department of Job and Family Services.

• These researchers, companies and/or organization(s) outside of The Ohio State University may also use, share and receive your health information in connection with this study: • None The information that is shared with those listed above may no longer be protected by federal privacy rules.

This research project was awarded a grant from the American Association of Endodontists Foundation. This grant helps with the financial cost of conducting the study. The American Association of Endodontists Foundation is not a stakeholder in the design or results of this study.

Authorization Period

This authorization will not expire unless you change your mind and revoke it in writing. There is no set date at which your information will be destroyed or no longer used. This is because the information used and created during the study may be analyzed for many years, and it is not possible to know when this will be completed.

Initials/Date______110

Signing the Authorization

• You have the right to refuse to sign this authorization. Your health care outside of the study, payment for your health care, and your health care benefits will not be affected if you choose not to sign this form. • You will not be able to take part in this study and will not receive any study treatments if you do not sign this form. • If you sign this authorization, you may change your mind at any time. Researchers may continue to use information collected up until the time that you formally changed your mind. If you change your mind, your authorization must be revoked in writing. To revoke your authorization, please write to: Dr. Melissa Drum at the College of Dentistry, 305 w 12th avenue, the Ohio State University, Columbus, Ohio 43218 or Dr. Henry Fischbach at the College of Dentistry, 305 w 12th avenue, the Ohio State University, Columbus, Ohio 43218. • Signing this authorization also means that you will not be able to see or copy your study- related information until the study is completed. This includes any portion of your medical records that describes study treatment.

Contacts for Questions

• If you have any questions relating to your privacy rights, please contact: Dr. Henry Fischbach at the College of Dentistry, 305 w 12th avenue, the Ohio State University, Columbus, Ohio 43218. Phone:(614)292-6983. • If you have any questions relating to the research, please contact: Dr. Melissa Drum at the College of Dentistry, 305 W. 12th Ave., The Ohio State University, Columbus, OH 43210. Phone:(614)292-3596.

Signature

I have read (or someone has read to me) this form and have been able to ask questions. All of my questions about this form have been answered to my satisfaction. By signing below, I permit Dr. Melissa Drum and the others listed on this form to use and share my personal health information for this study. I will be given a copy of this signed form.

Signature______(Subject or Legally Authorized Representative)

Print Name ______Date______Time ______AM/PM

______(If legal representative, also print relationship to subject)

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Appendix G Injection Pain VAS

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Code Number:______

Anesthetic Injection Pain Rating Insertion

Mark an “x” on the point on the line that best describes your pain.

None Faint Weak Mild Moderate Strong Intense Maximum Possible

Anesthetic Injection Pain Rating Placement

Mark an “x” on the point on the line that best describes your pain.

None Faint Weak Mild Moderate Strong Intense Maximum Possible

Anesthetic Injection Pain Rating Deposition

Mark an “x” on the point on the line that best describes your pain.

None Fa int Weak Mild Moderate Strong Intense Maximum Possible

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Appendix H Treatment Pain VAS

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Code Number:______

Emergency Treatment Access Dentin

Mark an “x” on the point on the line that best describes your pain.

None Faint Weak Mild Moderate Strong Intense Maximum Possible

Emergency Treatment Pulp Chamber

Mark an “x” on the point on the line that best describes your pain.

None Faint Weak Mild Moderate Strong Intense Maximum Possible

Emergency Treatment Instrument Canals

Mark an “x” on the point on the line that best describes your pain.

None Faint Weak Mild Moderate Strong Intense Maximum Possible

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Appendix I Anesthesia Grade

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CLINICAL PROCEDURE

11. Anesthesia Grade (Rate A-D): circle one Grade A (profoundly numb) Grade B (numb, some discomfort) Grade C (not numb, felt discomfort, able to complete treatment) Grade D (not numb, felt discomfort, had to re-inject)

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Appendix J Patient Pain Journal

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PATIENT SURVEY CODE# ______TOOTH# ______EVENING DAY 0 DATE ___-__-___ Day of root canal therapy COMPLETE BEFORE GOING TO BED; WHAT TIME IS IT ?___:___PM

A. Do you have any pain? (Mark an “x” on the point on the line that best describes your pain.)

None Faint Weak Mild Moderate Strong Intense Maximum

B. Is the pain getting better or worse or staying the same? Better___ Worse___ Same___

C. Have you taken any pain medication within the past 24 hours? Yes___ No___ If yes, how many tablets of pain medication have you taken? Number of ibuprofen____ Number of Tylenol #3 tablets ____

D. Do you have any swelling? (Mark an “x” on the point of the line that best describes it).

None Faint Weak Mild Moderate Strong Intense Maximum

0. None (no swelling). 1. Faint (no visible swelling, but a slight feeling of pressure inside my mouth). 2. Weak (slight swelling inside my mouth , but no visible swelling outside of my mouth, i.e., in the cheek or jaw). 3. Mild (slight puffiness of the cheek or jaw that is noticeable, but not bothersome). 4. Moderate (moderate puffiness of the cheek or jaw, or facial distortion that is noticeable and bothersome). 5. Strong (moderate-to-severe swelling of the cheek or jaw that is very noticeable and very bothersome). 6. Intense (severe swelling affecting more than the cheek or jaw that is very noticeable and very bothersome, limiting normal movement and function). 7. Maximum possible (Severe swelling that inhibits breathing, swallowing or eye opening, requiring emergency care).

E. Is the swelling getting better or worse or staying the same? Better___ Worse___ Same___

F.Comments______

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PATIENT SURVEY CODE# ______TOOTH# ______MORNING DAY 1 DATE ___-__-___ First day after root canal therapy COMPLETE AFTER ARISING; WHAT TIME IS IT ?___:___AM

A. Do you have any pain? (Mark an “x” on the point on the line that best describes your pain.)

None Faint Weak Mild Moderate Strong Intense Maximum

B. Is the pain getting better or worse or staying the same? Better___ Worse___ Same___

C. Have you taken any pain medication since completing the survey last night? Yes___ No___ If yes, how many tablets of pain medication have you taken? Number of ibuprofen____ Number of Tylenol #3 tablets ____

D. Do you have any swelling? (Mark an “x” on the point of the line that best describes it).

None Faint Weak Mild Moderate Strong Intense Maximum

0. None (no swelling). 1. Faint (no visible swelling, but a slight feeling of pressure inside my mouth). 2. Weak (slight swelling inside my mouth , but no visible swelling outside of my mouth, i.e., in the cheek or jaw). 3. Mild (slight puffiness of the cheek or jaw that is noticeable, but not bothersome). 4. Moderate (moderate puffiness of the cheek or jaw, or facial distortion that is noticeable and bothersome). 5. Strong (moderate-to-severe swelling of the cheek or jaw that is very noticeable and very bothersome). 6. Intense (severe swelling affecting more than the cheek or jaw that is very noticeable and very bothersome, limiting normal movement and function). 7. Maximum possible (Severe swelling that inhibits breathing, swallowing or eye opening, requiring emergency care).

E. Is the swelling getting better or worse or staying the same? Better___ Worse___ Same___

F.Comments______

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PATIENT SURVEY CODE# ______TOOTH# ______MORNING DAY 2 DATE ___-__-___ Second day after root canal therapy COMPLETE AFTER ARISING; WHAT TIME IS IT ?___:___AM

A. Do you have any pain? (Mark an “x” on the point on the line that best describes your pain.)

None Faint Weak Mild Moderate Strong Intense Maximum

B. Is the pain getting better or worse or staying the same? Better___ Worse___ Same___

C. Have you taken any pain medication within the past 24 hours? Yes___ No___ If yes, how many tablets of pain medication have you taken? Number of ibuprofen____ Number of Tylenol #3 tablets ____

D. Do you have any swelling? (Mark an “x” on the point of the line that best describes it).

None Faint Weak Mild Moderate Strong Intense Maximum

0. None (no swelling). 1. Faint (no visible swelling, but a slight feeling of pressure inside my mouth). 2. Weak (slight swelling inside my mouth , but no visible swelling outside of my mouth, i.e., in the cheek or jaw). 3. Mild (slight puffiness of the cheek or jaw that is noticeable, but not bothersome). 4. Moderate (moderate puffiness of the cheek or jaw, or facial distortion that is noticeable and bothersome). 5. Strong (moderate-to-severe swelling of the cheek or jaw that is very noticeable and very bothersome). 6. Intense (severe swelling affecting more than the cheek or jaw that is very noticeable and very bothersome, limiting normal movement and function). 7. Maximum possible (Severe swelling that inhibits breathing, swallowing or eye opening, requiring emergency care).

E. Is the swelling getting better or worse or staying the same? Better___ Worse___ Same___

F.Comments______

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PATIENT SURVEY CODE# ______TOOTH# ______MORNING DAY 3 DATE ___-__-___ Third day after root canal therapy COMPLETE AFTER ARISING; WHAT TIME IS IT ?___:___AM

A. Do you have any pain? (Mark an “x” on the point on the line that best describes your pain.)

None Faint Weak Mild Moderate Strong Intense Maximum

B. Is the pain getting better or worse or staying the same? Better___ Worse___ Same___

C. Have you taken any pain medication within the past 24 hours? Yes___ No___ If yes, how many tablets of pain medication have you taken? Number of ibuprofen____ Number of Tylenol #3 tablets ____

D. Do you have any swelling? (Mark an “x” on the point of the line that best describes it).

None Faint Weak Mild Moderate Strong Intense Maximum

0. None (no swelling). 1. Faint (no visible swelling, but a slight feeling of pressure inside my mouth). 2. Weak (slight swelling inside my mouth , but no visible swelling outside of my mouth, i.e., in the cheek or jaw). 3. Mild (slight puffiness of the cheek or jaw that is noticeable, but not bothersome). 4. Moderate (moderate puffiness of the cheek or jaw, or facial distortion that is noticeable and bothersome). 5. Strong (moderate-to-severe swelling of the cheek or jaw that is very noticeable and very bothersome). 6. Intense (severe swelling affecting more than the cheek or jaw that is very noticeable and very bothersome, limiting normal movement and function). 7. Maximum possible (Severe swelling that inhibits breathing, swallowing or eye opening, requiring emergency care).

E. Is the swelling getting better or worse or staying the same? Better___ Worse___ Same___

F.Comments______

122

PATIENT SURVEY CODE# ______TOOTH# ______MORNING DAY 4 DATE ___-__-___ Fourth day after root canal therapy COMPLETE AFTER ARISING; WHAT TIME IS IT ?___:___AM

A. Do you have any pain? (Mark an “x” on the point on the line that best describes your pain.)

None Faint Weak Mild Moderate Strong Intense Maximum

B. Is the pain getting better or worse or staying the same? Better___ Worse___ Same___

C. Have you taken any pain medication within the past 24 hours? Yes___ No___ If yes, how many tablets of pain medication have you taken? Number of ibuprofen____ Number of Tylenol #3 tablets ____

D. Do you have any swelling? (Mark an “x” on the point of the line that best describes it).

None Faint Weak Mild Moderate Strong Intense Maximum

0. None (no swelling). 1. Faint (no visible swelling, but a slight feeling of pressure inside my mouth). 2. Weak (slight swelling inside my mouth , but no visible swelling outside of my mouth, i.e., in the cheek or jaw). 3. Mild (slight puffiness of the cheek or jaw that is noticeable, but not bothersome). 4. Moderate (moderate puffiness of the cheek or jaw, or facial distortion that is noticeable and bothersome). 5. Strong (moderate-to-severe swelling of the cheek or jaw that is very noticeable and very bothersome). 6. Intense (severe swelling affecting more than the cheek or jaw that is very noticeable and very bothersome, limiting normal movement and function). 7. Maximum possible (Severe swelling that inhibits breathing, swallowing or eye opening, requiring emergency care).

E. Is the swelling getting better or worse or staying the same? Better___ Worse___ Same___

F.Comments______

123

PATIENT SURVEY CODE# ______TOOTH# ______MORNING DAY 5 DATE ___-__-___ Fifth day after root canal therapy COMPLETE AFTER ARISING; WHAT TIME IS IT ?___:___AM

A. Do you have any pain? (Mark an “x” on the point on the line that best describes your pain.)

None Faint Weak Mild Moderate Strong Intense Maximum

B. Is the pain getting better or worse or staying the same? Better___ Worse___ Same___

C. Have you taken any pain medication within the past 24 hours? Yes___ No___ If yes, how many tablets of pain medication have you taken? Number of ibuprofen____ Number of Tylenol #3 tablets ____

D. Do you have any swelling? (Mark an “x” on the point of the line that best describes it).

None Faint Weak Mild Moderate Strong Intense Maximum

0. None (no swelling). 1. Faint (no visible swelling, but a slight feeling of pressure inside my mouth). 2. Weak (slight swelling inside my mouth , but no visible swelling outside of my mouth, i.e., in the cheek or jaw). 3. Mild (slight puffiness of the cheek or jaw that is noticeable, but not bothersome). 4. Moderate (moderate puffiness of the cheek or jaw, or facial distortion that is noticeable and bothersome). 5. Strong (moderate-to-severe swelling of the cheek or jaw that is very noticeable and very bothersome). 6. Intense (severe swelling affecting more than the cheek or jaw that is very noticeable and very bothersome, limiting normal movement and function). 7. Maximum possible (Severe swelling that inhibits breathing, swallowing or eye opening, requiring emergency care).

E. Is the swelling getting better or worse or staying the same? Better___ Worse___ Same___

F.Comments______

124

PATIENT SURVEY CODE# ______TOOTH# ______MORNING DAY 6 DATE ___-__-___ Sixth day after root canal therapy COMPLETE AFTER ARISING; WHAT TIME IS IT ?___:___AM

A. Do you have any pain? (Mark an “x” on the point on the line that best describes your pain.)

None Faint Weak Mild Moderate Strong Intense Maximum

B. Is the pain getting better or worse or staying the same? Better___ Worse___ Same___

C. Have you taken any pain medication within the past 24 hours? Yes___ No___ If yes, how many tablets of pain medication have you taken? Number of ibuprofen____ Number of Tylenol #3 tablets ____

D. Do you have any swelling? (Mark an “x” on the point of the line that best describes it).

None Faint Weak Mild Moderate Strong Intense Maximum

0. None (no swelling). 1. Faint (no visible swelling, but a slight feeling of pressure inside my mouth). 2. Weak (slight swelling inside my mouth , but no visible swelling outside of my mouth, i.e., in the cheek or jaw). 3. Mild (slight puffiness of the cheek or jaw that is noticeable, but not bothersome). 4. Moderate (moderate puffiness of the cheek or jaw, or facial distortion that is noticeable and bothersome). 5. Strong (moderate-to-severe swelling of the cheek or jaw that is very noticeable and very bothersome). 6. Intense (severe swelling affecting more than the cheek or jaw that is very noticeable and very bothersome, limiting normal movement and function). 7. Maximum possible (Severe swelling that inhibits breathing, swallowing or eye opening, requiring emergency care).

E. Is the swelling getting better or worse or staying the same? Better___ Worse___ Same___

F.Comments______

125

PATIENT SURVEY CODE# ______TOOTH# ______MORNING DAY 7 DATE ___-__-___ Seventh day after root canal therapy COMPLETE AFTER ARISING; WHAT TIME IS IT ?___:___AM

A. Do you have any pain? (Mark an “x” on the point on the line that best describes your pain.)

None Faint Weak Mild Moderate Strong Intense Maximum

B. Is the pain getting better or worse or staying the same? Better___ Worse___ Same___

C. Have you taken any pain medication within the past 24 hours? Yes___ No___ If yes, how many tablets of pain medication have you taken? Number of ibuprofen____ Number of Tylenol #3 tablets ____

D. Do you have any swelling? (Mark an “x” on the point of the line that best describes it).

None Faint Weak Mild Moderate Strong Intense Maximum

0. None (no swelling). 1. Faint (no visible swelling, but a slight feeling of pressure inside my mouth). 2. Weak (slight swelling inside my mouth , but no visible swelling outside of my mouth, i.e., in the cheek or jaw). 3. Mild (slight puffiness of the cheek or jaw that is noticeable, but not bothersome). 4. Moderate (moderate puffiness of the cheek or jaw, or facial distortion that is noticeable and bothersome). 5. Strong (moderate-to-severe swelling of the cheek or jaw that is very noticeable and very bothersome). 6. Intense (severe swelling affecting more than the cheek or jaw that is very noticeable and very bothersome, limiting normal movement and function). 7. Maximum possible (Severe swelling that inhibits breathing, swallowing or eye opening, requiring emergency care).

E. Is the swelling getting better or worse or staying the same? Better___ Worse___ Same___

F.Comments______

126