ORIGINAL ARTICLE

Aspirin, acetaminophen, and ibuprofen: Their

effects on orthodontic tooth movement
Oscar R. Ariasa and Maria C. Marquez-Orozcob
México DF, Mexico

Introduction: Orthodontic patients often take analgesics for pain during treatment. But various analgesics
have different capacities to inhibit prostaglandins, and these differences might affect tooth movement. The
purposes of this study were to determine by direct measurement the effects that acetylsalicylic acid,
ibuprofen, and acetaminophen have on orthodontic tooth movement in rats and to evaluate histologically the
differences in bone resorption in the pressure area in rats treated with these analgesics. Methods: Thirty-six
adult male Wistar rats were divided in 4 groups of 9 each. Orthodontic appliances were placed on the rats’
incisors. In the 3 experimental groups, analgesics were diluted in reverse osmosis water and delivered via a
gastric tube: 100 mg/kg acetylsalicylic acid, or 30 mg/kg ibuprofen, or 200 mg/kg acetaminophen. Control
animals received only the reverse osmosis water. At the end of the experimental period, the rats were killed
and histological examinations were performed. Results: Analysis of variance showed statistically significant
differences between the control group, which was given reverse osmosis water, and the groups given aspirin
and ibuprofen. There were also statistically significant differences between the acetaminophen group and the
ibuprofen and aspirin groups, respectively. There was no significant difference between the acetaminophen
group and the control group, or between the aspirin and ibuprofen groups. Tooth movement was similar
in the groups. Conclusions: The results indicate that nonsteroidal anti-inflammatory analgesics such as
aspirin and ibuprofen diminish the number of osteoclasts, probably by inhibiting the secretion of
prostaglandins, thereby reducing orthodontic tooth movement. Acetaminophen did not affect orthodontic
tooth movement in rats, and it might be the analgesic of choice for treating pain associated with orthodontic
treatment. (Am J Orthod Dentofacial Orthop 2006;130:364-70)

O
rthodontists often suggest that patients, in the
first days after each visit, take analgesics for
pain from the appliances used for orthodontic
tooth movement.1-3 Most of these drugs are nonsteroi-
dal anti-inflammatories with analgesic and antipyretic
action. The anti-inflammatory effects result from the
inhibition of the biosynthesis of prostaglandins (PGs)
when they act over the cyclo-oxygenase involved in
catabolism of arachidonic acid, present in the phospho-
lipidic membrane of cells.4,5 The cellular damage, or
the nondestructive disruption of the membrane, and the
orthodontic tooth movement activates phospholipase,
which induces the liberation of PGs.6,7
There is evidence that PGs play an important role as
balancing agents in bone remodeling induced by me-
chanical stress.8-20 PGs of the E and F series have been
From the Department of Orthodontics, Universidad Intercontinental,
México DF, Mexico.
a
Orthodontist, private practice, Guatemala City, Guatemala.
b
Professor of embryology; professor of embryology and genetics, Department
of Medicine, Universidad Nacional Autonóma de México, México DF, Mexico.
Reprint requests to: Oscar R. Arias, 1000 NW 17th St, #102, Box 513, Miami,
FL 33172; e-mail, ariasoscar@hotmail.com.
Submitted, October 2004; revised and accepted, December 2004.
0889-5406/$32.00
Copyright © 2006 by the American Association of Orthodontists.
doi:10.1016/j.ajodo.2004.12.027
364
implicated in bone remodeling activities, particularly
resorption; they decrease collagen synthesis and in-
crease cyclic adenosine monophosphate (AMP). Over
the past 2 decades, several researchers studied the
relationship between PGs and tooth movement.15,16
Animal studies showed that the tooth movement index
significantly increases when PGs are injected.6,7 On the
other hand, it has been reported that indomethacin and
flurbiprofen—which are specific inhibitors of PGs—
reduce the amount of osteoclasts in the alveolar bones
of cats and rabbits receiving orthodontic forces and also
reduce the dental movement index by 50%.8,21 Chum-
bley and Tuncay21 recommended that patients having
orthodontic treatment should void aspirin and other
nonsteroidal anti-inflammatory analgesics because they
can prolong treatment.
Acetaminophen is a nonsteroidal anti-inflammatory drug
in the family of paraminophenols, which by not inhibiting
PGs or by inhibiting them slightly, should not have an effect
on orthodontic tooth movement. Its antipyretic and analgesic
activities are the same as aspirin. However, its mechanism of
action has not been determined, and it is supposed that its
analgesic effect is produced at the central nervous
system level and does not act over cell membranes, as
those described previously do.22
American Journal of Orthodontics and Dentofacial Orthopedics
Volume 130, Number 3
The purposes of this study were to determine how 3
commonly used analgesics affect orthodontic tooth
movement and to compare their histologic effects.
MATERIAL AND METHODS
Adult male Wistar albino rats, 12 weeks old and
weighing 250 to 300 g, were raised and housed in the
Biomedic Research Institute of the Universidad Nacio-
nal Autónoma de México. The rats were kept in
polycarbonate boxes at temperatures between 19°C and
22°C, and humidity of 40% to 50%, in a photoperiod of
12/12 hours starting at 7 am. They were fed pellets
(Harlan Teklad, Harlan 702, Los Angeles, Calif)) and
water ad libitum.
The animals were divided randomly into 3 experi-
mental groups and 1 control group (9 per group). The
analgesics were administered through a gastric tube
every 12 hours for 10 days, diluted in 0.6 mL of reverse
osmosis filtered water. Group 1 received 100 mg per
kilogram of acetylsalicylic acid (aspirin, 500 mg);
group 2 received 30 mg per kilogram of ibuprofen
(Motrin [Johnson & Johnson, New Brunswick, NJ],
400 mg); group 3 received 200 mg per kilogram of
acetaminophen (Tylenol [Johnson & Johnson, New
Brunswick, NJ], 500 mg); group 4, the control group,
received 0.6 mL of reverse osmosis filtered water. The
rats’ weights were recorded every morning at the same
time.
To prepare the aspirin solution, two 500-mg tablets
were dissolved in 20 mL of reverse osmosis filtered
water. To prevent solution hydrolysis, the aspirin solu-
tion was prepared before each use.23 The Motrin and
Tylenol solutions were prepared by dissolving one
400-mg tablet of Motrin and four 500-mg tablets of
Tylenol in 26.6 and 20 mL, respectively, of reverse
osmosis filtered water. These solutions were stable and
were stored at room temperature until use.24
The orthodontic appliance was a 3-spin loop, 2 mm
in diameter, with arms 12 mm in length, with “V” folds
placed 9 mm from the coil region, made of 0.016-in
beta-titanium alloy wire. A dynamometer (Correx gauge,
Haag-Streit, Switzerland) was used to measure the 35 g of
tension.
The rats were anesthetized by using the dissociative
technique, which consists of giving a dose of ketamine
(Imalgen, Rhone Meriux, Athens, Ga), 90 mg per
kilogram IM (intramuscular), followed of a dose of
xilazine hydrochloride (Rompúm, Bayer, Germany) of
10 mg per kilogram IP (intraperitonial). The incisors
were drilled in the gingival third from the vestibule
to the palate with a quarter-inch carbon bur. The
arms of the appliance passed from palate to vesti-
bule. To keep the appliance in place, a photocurable
Arias and Marquez-Orozco 365
resin cover, Ortho LC (Fuji, GC America, Inc, Alsip,
Ill), etched with 37% orthophosphoric acid for 2
minutes and washed with sterilized water, was used.
The appliance was kept in this position for 10 days.
Before the appliances were placed, it was deter-
mined that there was no measurable space between the
maxillary incisors. Measurements of incisor separation
were recorded at the same time in the morning, by
using a caliper accurate to .01 mm. Measurements were
made by 2 observers who were blinded to treatment
allocation; they recorded the average from 3 assays
from days 1 to 10 of the study.
Analysis of variance (ANOVA) was performed
along with the Tukey test to determine whether there
were statistically significant differences between the
experimental groups (P ⬍.05).
Histologic study
The rats were killed with carbon dioxide inhalation
and decapitated, and the heads were dried. Each pre-
maxilla was placed in 10% neutral formaline for 24
hours and then rinsed with water. Because of the high
calcium content, the osseo-dentary blocks were not cut
directly in the microtome. They were decalcified for
approximately 3 weeks in a 12.5% EDTA aqueous
solution. The cuts were 7 ␮m thick. They were placed
in paraffin by using conventional methodology and
stained with Harris-eosin hematoxylin. A comparison
electron microscope was used to count randomly, with
a micrometric grid, the number of osteoclastic cells per
area in different samples. The histologic study focused
on the interradicular bone located between the superior
incisors from the alveolar crest up to the apices of the
teeth, to 10 sections per specimen. An operator, blinded
to treatment allocation, recorded data in a randomly
selected area of 800 ⫻ 400 ␮2. The histologic criterion
to identify the osteoclasts was the presence of multinu-
clear and eosinophylic cells on the bone surface. Data
were processed by using a variance analysis to deter-
mine whether there were differences between the con-
trol group and the experimental groups (P ⬍.05).
RESULTS
It was observed from the histologic maxillary cuts,
made 3 mm from the palatine border of the incisors of the
rats in the control group, that the pressure area of the
moved teeth was trabecular, because of large bone remod-
eling areas characterized by great absorption lacunae, in
which numerous multinuclear osteoclasts, mainly in the
periphery of the absorption lacunae, were found. Star cells
of the mesenchymal type were found in the interior of the
lacunae, undifferentiated and next to the wall; they were
osteoblasts that began depositing osteoid material. Around
366 Arias and Marquez-Orozco
Fig 1. Alveolar bone from pressure zone of superior
incisor of rat from control group (reverse osmosis
filtered water). Normal structure of resorption area (r),
osteoblasts (ob), osteoclasts (oc), osteocytes (os),
growth lines (c), and osseous matrix (m). Hematoxylin-
eosin staining, original magnification 450 X.
the lacunae, the trabeculae were made of osseous matrix,
not too stained from the eosin-hematoxylin technique in
which osteocytes that appeared normal were included. In
the matrix, it was observed that there were numerous bone
growth lines, that frequently were concentric around the
osteonas. Both the growth lines and the resorption areas
were more abundant near the periodontal ligament than at
the bone’s periphery (Fig 1).
In the acetaminophen group, the features of the
alveolar bone in the pressure area of the orthodontically
moved teeth showed that the histologic structure was
similar to that in the control group, because it also had
abundant remodeling areas, with characteristic oste-
oclasts, osteogenic cells with mesequimatic appear-
ance, and epithelial osteoblasts. The bone trabeculae
appeared normal (Fig 2).
In the aspirin group, the bone had few remodeled
areas, which were small and had few osteoblasts on the
periphery, and it was difficult to identify the oste-
oclasts. The osteocytes were distributed in parallel
layers and on average were more abundant than in the
control group. There were no growth lines observed
around the osteonas (Fig 3).
The bones of the rats that received ibuprofen also
American Journal of Orthodontics and Dentofacial Orthopedics
September 2006
Fig 2. Alveolar bone from pressure zone of superior
incisor of rat treated with acetaminophen. Note large
resorption areas (r), with abundant osteoblasts (ob),
well-differentiated osteoclasts (oc), osteocytes (os) on
growth lines (c) and in abundant osseous matrix (m).
Hematoxylin-eosin staining, original magnification 450 X.
had few remodeling areas and growth lines. On aver-
age, the osteoblasts and osteoclasts were very few. The
osteocytes were aligned, even though there were fewer
than in rats treated with aspirin (Fig 4).
ANOVA showed that there were statistically sig-
nificant differences (P ⬍.05) in the concentrations of
osteoclasts on the pressure areas of teeth receiving
orthodontic forces in rats treated with aspirin (1.83 ⫾
1.18) or ibuprofen (2.48 ⫾ 2.25) compared with the
control group (14.02 ⫾ 5.27) and the group treated with
acetaminophen (13.43 ⫾ 4.31). In contrast, the number
of osteoclasts was not significantly different between
the acetaminophen and the control groups, or the
groups treated with aspirin or ibuprofen (P ⬎.05)
(Table I). The same results were found when analyzing
the osseous resorption areas: 6.09 ⫾ 1.61 in the control
group, 5.86 ⫾ 1.52 in the acetaminophen group, 1.86 ⫾
1.15 in the aspirin group, and 2.00 ⫾ 1.61 in the
ibuprofen group (Table I).
Average tooth movement was recorded cumula-
tively during the study period; ANOVA showed a
significant statistical difference between the group
treated with nonsteroid anti-inflammatory analgesics
and the control group (P ⬍.01). A 1-tailed Tukey
American Journal of Orthodontics and Dentofacial Orthopedics
Volume 130, Number 3
Fig 3. Alveolar bone from pressure zone of superior
incisor of rat treated with aspirin. Note small resorption
areas (r), with few osteoblasts (ob) and abundant osteo-
cytes (os) stacked in layers, in parallel lines. Hematox-
ylin-eosin staining, original magnification 450 X.
analysis, at P ⬍.05, was done to compare the measure-
ments of the groups (mm), and statistically significant
differences were found between the control group, with
movement of 1.86 ⫾ 0.53, and the aspirin group, with
movement of 1.32 ⫾ 0.28, and the ibuprofen group,
with movement of 1.22 ⫾ 0.29. The control group
compared with the acetaminophen group, with move-
ment of 1.80 ⫾ 0.41, was similar, and there was no
statistically significant difference between both (P
⬎.05). There was a statistically significant difference
between the acetaminophen group and the aspirin or
ibuprofen groups (P ⬍.05) (Table II).
The control and acetaminophen groups compared
with the aspirin or ibuprofen group showed a difference
in the amount of tooth movement throughout the 10
days (P ⬍.05). However, when the ANOVA test was
done day by day for the 4 treatments, it was found
that the differences were not statistically significant
(P ⬎.05) 1 day after giving the medicine or the reverse
osmosis filtered water. However, there were statisti-
cally significant differences on the second day (P ⬍.03)
and the third day (P ⬍.010), and from the fourth day on
(P ⬍.0001) (Table II).
When applying ANOVA to the rats’ daily weight
data recorded during the experiment, there were no
Arias and Marquez-Orozco 367
Fig 4. Alveolar bone from pressure zone of superior
incisor of rat treated with ibuprofen, with fewer resorp-
tion areas (r), and few osteoblasts (ob), osteoclasts (oc),
and osteocytes (os) in osseous matrix (m). Hematoxylin-
eosin staining, original magnification 450 X.
statistically significant differences (P ⬎.05) between
the control group and the experimental groups, or
among experimental groups, even though the rats in the
experimental groups lost weight, especially the day
after treatment began.
DISCUSSION
When the interpremaxillary suture is fused in adult
rats, the separation of the maxillary incisors occurs
because of orthodontic movement and not orthopedic
movement.25 This was confirmed with initial and final
x-rays (Fig 5) in a pilot study. Although the teeth have
a continuous eruption pattern, the disposition of the
periodontal structures is similar to that in humans, and
incisors respond readily to orthodontic mechanother-
apy. Therefore, adult rats were used in this study; to
eliminate the effects of hormonal variability, only male
rats were used.26
Fewer osteoclasts were observed in the pressure
area of the orthodontically moved incisors in rats
treated with aspirin or ibuprofen, compared with the
control group and the group treated with acetamino-
phen. The reason for this could be that the first 2
analgesics inhibit in a greater way the production of
PGs, which stimulate the activation of osteoclasts in the
368 Arias and Marquez-Orozco
Table I. Number of resorption areas and osteoclasts in
pressure side of alveolar bone of orthodontically treated
teeth in rats (P ⬎.05)
Resorption areas Osteoclasts
Group Mean ⫾ SD Mean ⫾ SD
Control 6.09 1.61 14.02 5.27
Acetaminophen 5.86 1.52 13.43 4.31
Aspirin 1.86 1.15 1.83 1.18
Ibuprofen 2.00 1.61 2.48 2.25
bone and the development of more PGs. When there
were not enough osteoclasts, bone resorption was also
reduced; therefore, teeth moved less on average. The
results are inverse from those of Yamasaki et al,15 who
increased tooth movement when injecting PGs in the
pressure areas of canines in orthodontic patients. Lee16
introduced PGs, both locally and systemically, in
guinea pigs and observed a significant increase in the
number of osteoclasts in the pressure areas of orthodon-
tic tooth movement. The study of Davidovitch and
Shanfeld14with cats showed that PGs were responsible
for bone resorption during tooth movement.
Based on previous studies, Wong et al23 proposed
that aspirin does not modify orthodontic tooth move-
ment in guinea pigs. However, the dose of analgesic
used was lower than the dose necessary to reduce pain
and the secretion of PGs in these animals, which have
a faster metabolic rate than humans and require higher
doses than the therapeutic one to produce the same
pharmacological action.27-29 On the other hand, the
force they used to move the teeth was 8 g, which,
according to the study of King,30 was not enough. King
found that, for rats, the optimum force for this proce-
dure was 20 to 40 g, which might be similar to that
required for guinea pigs. When applying only 8 g of
force, probably there was so little movement that the
differences were too small to detect. According to
King,30 the tooth-movement curve in rats treated orth-
odontically has 3 parts that represent distinctly different
processes. The initial movement begins almost instan-
taneously and is a reflection of tissue deformation. The
second phase is a delay in movement, which reflects
recruitment of cells and the establishment of a micro-
environment that will allow the appropriate tissue
modeling and remodeling. The final phase is tissue
turnover to allow reduction of the applied strain terminat-
ing in appliance deactivation.30 This finding is similar to
that described by Burstone31 in 1962; he suggested that
there are 3 phases of orthodontic tooth movement: an
initial phase, representing the displacement of the tooth in
the periodontal membrane space; the lag phase, when the
American Journal of Orthodontics and Dentofacial Orthopedics
September 2006
tooth did not move or had a relatively low rate of
displacement; and the postlag phase, when the rate of
movement gradually or suddenly increased.
In our investigation, the daily ANOVA for the 4
treatments showed that the differences were not statis-
tically significant (P ⬎.05) 1 day after giving the
medicine or the reverse osmosis filtered water. How-
ever, there were statistically significant differences on
the second (P ⬍.03) and third (P ⬍.010) days, and
from the fourth day on (P ⬍.0001) (Table II).
According to these results, it can be suggested that
in the first 4 days the dental movement of rat incisors
was in the initial and lag phases. In the last 6 days, it
could be said that the osteoclasts were suppressed in their
maximum expression, and there was reduced movement
in the groups that received aspirin and ibuprofen. How-
ever, a study is needed in which osteoclasts are counted
each day to support these suggestions.
Acetaminophen acts over central nervous system
without inhibiting the secretion of periphery PGs.22
This could explain the presence of osteoclasts in the
pressure area of the moved incisors equivalent to that of
the control groups, as well as bone resorption lacunae
and dental movement, which were also similar.
Because we used adult rats in this study, the
regeneration of the alveolar bone was less than that of
younger animals. Therefore, the findings in the control
and acetaminophen groups that bone is actively regen-
erating as if the rats were young can be assumed to be
caused by orthodontic treatment activating the secretion
of PGs and the osteoclasts that act in bone resorption
This did not happen in the groups treated with aspirin
and ibuprofen; the bone had fewer resorption lacunae
and osteoclasts, which showed the compact bone char-
acteristics of an adult. Even though local levels of PGs
were not measured, our results showed indirectly that
both analgesics inhibit their secretion.
An indirect proof of the inhibition of PGs was the
reduced movement of teeth in rats treated with aspirin
and ibuprofen, compared with the controls. On the
other hand, when no significant differences were ob-
served between the control group and the acetamino-
phen group, the theory that acetaminophen does not
inhibit periphereal secretion of PGs is supported, coin-
ciding with the findings of Bianchi.22
CONCLUSIONS
1. Ibuprofen and aspirin significantly (P ⬍.01) re-
duced the numbers of resorption lacunae and oste-
oclasts in the pressure areas of orthodontic tooth
movement, compared with the control and acet-
aminophen groups.
American Journal of Orthodontics and Dentofacial Orthopedics Arias and Marquez-Orozco 369
Volume 130, Number 3

Table II. Comparison of cumulative dental movement during study period (P ⬎.05)
Control Aspirin Acetaminophen Ibuprofen

Day Mean ⫾ SD Mean ⫾ SD Mean ⫾ SD Mean ⫾ SD

1 1.11 0.24 0.85 0.41 1.19 0.27 0.71 0.39

2* 1.38 0.41 1.07 0.38 1.40 0.21 0.89 0.44
3† 1.58 0.22 1.16 0.24 1.55 0.21 1.11 0.26
4‡ 1.67 0.24 1.23 0.25 1.63 0.21 1.18 0.25
5 1.62 0.33 1.16 0.24 1.50 0.44 1.11 0.17
6 1.77 0.35 1.44 0.36 1.84 0.36 1.24 0.20
7 1.94 0.31 1.51 0.37 2.07 0.27 1.32 0.20
8 2.19 0.42 1.50 0.43 2.11 0.29 1.48 0.33
9 2.50 0.50 1.59 0.35 2.22 0.41 1.55 0.30
10 2.89 0.99 1.77 0.44 2.49 0.39 1.69 0.33

*P ⬍.031; †P ⬍.01; ‡P ⬍.0001.

7. Acetaminophen did not interfere with treatment in

Fig 5. Radiographs of premaxillary suture in rat: A,
before and B, after incisor separation.
2. Acetaminophen did not significantly (P ⬍.01) re-
duce the numbers of resorption lacunae and oste-
oclasts in the pressure area of the orthodontically
moved incisors. This result was similar to that of
the control group.
3. Orthodontic tooth movement during the 10 days of
the study was less in the rats treated with aspirin or
ibuprofen than in those in the control and acetamin-
ophen groups. The acetaminophen group had tooth
movement equivalent to that of the control group
(P ⬎.05).
4. In the rats in the control and acetaminophen groups,
alveolar bone was regenerating unimpeded, whereas,
in the aspirin and ibuprofen groups, regeneration was
compact.
5. The osseous characteristics and lower dental move-
ment in the aspirin and ibuprofen groups could be
due to the inhibition of PGs at the peripheral level.
6. Acetaminophen probably does not alter osseous
regeneration or dental movement because it acts at
the central nervous system level and does not affect
the peripheral secretion of PGs.
Wistar albino rats.
In this study, we analyzed the effects of nonsteroi-
dal anti-inflammatory drugs in animals. It would be
appropriate to design a research study to analyze the
effects of these drugs in humans receiving orthodontic
treatment.
It has been shown that PGs produce hyperalge-
sia.32,33 The drugs that inhibit the liberation of PGs are
a viable option to control pain after orthodontic treat-
ment. As the number of adults having orthodontic treat-
ment increases, the probability that they will take other
medicines for long periods of time also increases—
nonsteroidal anti-inflammatory drugs for arthritis, tri-
cyclic antidepressants, antiarrhythmics, antipaludic
agents, or methylxanthines, which are agonists or
antagonists of PGs and could cause unusual results after
the application of orthodontic forces.
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