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Aspirin, acetaminophen, and ibuprofen: Their effects on orthodontic tooth movement
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 nonsteroidal 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 phospholipidic 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 mechanical 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, [email protected]. 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
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implicated in bone remodeling activities, particularly resorption; they decrease collagen synthesis and increase 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 Chumbley 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
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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 Nacional 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 experimental 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 solution 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 vestibule. To keep the appliance in place, a photocurable
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 determined 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 premaxilla 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 multinuclear and eosinophylic cells on the bone surface. Data were processed by using a variance analysis to determine whether there were differences between the control 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 remodeling 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
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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). Hematoxylineosin staining, original magnification 450 X.
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.
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 osteoclasts, osteogenic cells with mesequimatic appearance, 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 osteoclasts. 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
had few remodeling areas and growth lines. On average, 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 significant 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 cumulatively 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
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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 osteocytes (os) stacked in layers, in parallel lines. Hematoxylin-eosin staining, original magnification 450 X.
Fig 4. Alveolar bone from pressure zone of superior incisor of rat treated with ibuprofen, with fewer resorption areas (r), and few osteoblasts (ob), osteoclasts (oc), and osteocytes (os) in osseous matrix (m). Hematoxylineosin staining, original magnification 450 X.
analysis, at P ⬍.05, was done to compare the measurements 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 movement 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 statistically 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
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 mechanotherapy. 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 acetaminophen. 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
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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 Acetaminophen Aspirin Ibuprofen
6.09 5.86 1.86 2.00
1.61 1.52 1.15 1.61
14.02 13.43 1.83 2.48
5.27 4.31 1.18 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 orthodontic 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 movement 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 procedure 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 orthodontically has 3 parts that represent distinctly different processes. The initial movement begins almost instantaneously 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 microenvironment that will allow the appropriate tissue modeling and remodeling. The final phase is tissue turnover to allow reduction of the applied strain terminating 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
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 statistically significant (P ⬎.05) 1 day after giving the medicine or the reverse osmosis filtered water. However, 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. However, 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 regenerating 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 characteristics 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 observed between the control group and the acetaminophen group, the theory that acetaminophen does not inhibit periphereal secretion of PGs is supported, coinciding with the findings of Bianchi.22 CONCLUSIONS
1. Ibuprofen and aspirin significantly (P ⬍.01) reduced the numbers of resorption lacunae and osteoclasts in the pressure areas of orthodontic tooth movement, compared with the control and acetaminophen groups.
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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 2* 3† 4‡ 5 6 7 8 9 10
1.11 1.38 1.58 1.67 1.62 1.77 1.94 2.19 2.50 2.89
0.24 0.41 0.22 0.24 0.33 0.35 0.31 0.42 0.50 0.99
0.85 1.07 1.16 1.23 1.16 1.44 1.51 1.50 1.59 1.77
0.41 0.38 0.24 0.25 0.24 0.36 0.37 0.43 0.35 0.44
1.19 1.40 1.55 1.63 1.50 1.84 2.07 2.11 2.22 2.49
0.27 0.21 0.21 0.21 0.44 0.36 0.27 0.29 0.41 0.39
0.71 0.89 1.11 1.18 1.11 1.24 1.32 1.48 1.55 1.69
0.39 0.44 0.26 0.25 0.17 0.20 0.20 0.33 0.30 0.33
*P ⬍.031; †P ⬍.01; ‡P ⬍.0001.
7. Acetaminophen did not interfere with treatment in Wistar albino rats.
Fig 5. Radiographs of premaxillary suture in rat: A, before and B, after incisor separation.
2. Acetaminophen did not significantly (P ⬍.01) reduce the numbers of resorption lacunae and osteoclasts 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 acetaminophen 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 movement 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.
In this study, we analyzed the effects of nonsteroidal 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 hyperalgesia.32,33 The drugs that inhibit the liberation of PGs are a viable option to control pain after orthodontic treatment. As the number of adults having orthodontic treatment increases, the probability that they will take other medicines for long periods of time also increases— nonsteroidal anti-inflammatory drugs for arthritis, tricyclic 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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8. Sandy JR, Harris M. Prostaglandins and tooth movement. Eur J Orthod 1984;6:175-82. 9. Utley K. The activity of alveolar bone incident to orthodontic tooth movement as studied by oxytetracycline-induced fluorescence. Am J Orthod 1968;54:167-70. 10. Breitner C. Bone changes resulting from experimental orthodontic treatment. Am J Orthod Oral Surg 1940;26:521-4. 11. Rodan GA, Yeh CK, Thompson DT. Prostaglandins and bone. In: Norton LA, Burstone CJ, editors. The biology of tooth movement. Boca Raton, Fla: CRC Press; 1989. p. 1111-24. 12. Saito M, Saito S, Ngan P, Shanfeld J, Davidovitch Z. Interleukin 1 beta and prostaglandin E are involved in the response of periodontal cells to mechanical stress in vivo and in vitro. Am J Orthod Dentofacial Orthop 1991;99:226-30. 13. Klein DC, Raisz LG. Prostaglandins: stimulation of bone resorption in tissue culture. Endocrinology 1970;86:1436-40. 14. Davidovitch Z, Shanfeld JL. Prostaglandin E2 (PGE2) levels in alveolar bone of orthodontically treated cats. IADR Progr & Abst 1980;59:977-85. 15. Yamasaki K, Shibata Y, Imai S, Tani Y, Shibasaki Y, Fukuhara T. Clinical application of prostaglandin E1 (PGE1) upon orthodontic tooth movement. Am J Orthod 1984;85:508-18. 16. Lee W. Experimental study of the effect of prostaglandin administration on tooth movement with particular emphasis on the relationship to the method of PGE1 administration. Am J Orthod Dentofacial Orthop 1990;98:231-41. 17. Santoro MG, Jaffe BM, Simmons DJ. Bone resorption in vitro and in vivo in PGE- treated mice. Proc Soc Exp Biol Med 1977;156:373-4. 18. Schelling SH, Wolfe HJ, Tashjian AH. Role of the osteoclast in prostaglandin E2-stimulated bone resorption. Lab Invest 1980; 42:290-5. 19. Raisz LG, Vanderhoek JY, Simmons HA. Prostaglandin synthesis by fetal rat bone in vitro: evidence for a role of prostacycline. Prostaglandins 1979;17:905-14. 20. Boekenoogen D, Sinha PK, Nanda RS, Ghosh J, Currier GF, Howes RI. The effects of exogenous prostaglandin E2 on root
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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 nonsteroidal 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 phospholipidic 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 mechanical 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, [email protected]. 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
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implicated in bone remodeling activities, particularly resorption; they decrease collagen synthesis and increase 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 Chumbley 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
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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 Nacional 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 experimental 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 solution 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 vestibule. To keep the appliance in place, a photocurable
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 determined 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 premaxilla 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 multinuclear and eosinophylic cells on the bone surface. Data were processed by using a variance analysis to determine whether there were differences between the control 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 remodeling 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
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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). Hematoxylineosin staining, original magnification 450 X.
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.
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 osteoclasts, osteogenic cells with mesequimatic appearance, 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 osteoclasts. 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
had few remodeling areas and growth lines. On average, 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 significant 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 cumulatively 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
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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 osteocytes (os) stacked in layers, in parallel lines. Hematoxylin-eosin staining, original magnification 450 X.
Fig 4. Alveolar bone from pressure zone of superior incisor of rat treated with ibuprofen, with fewer resorption areas (r), and few osteoblasts (ob), osteoclasts (oc), and osteocytes (os) in osseous matrix (m). Hematoxylineosin staining, original magnification 450 X.
analysis, at P ⬍.05, was done to compare the measurements 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 movement 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 statistically 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
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 mechanotherapy. 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 acetaminophen. 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
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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 Acetaminophen Aspirin Ibuprofen
6.09 5.86 1.86 2.00
1.61 1.52 1.15 1.61
14.02 13.43 1.83 2.48
5.27 4.31 1.18 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 orthodontic 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 movement 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 procedure 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 orthodontically has 3 parts that represent distinctly different processes. The initial movement begins almost instantaneously 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 microenvironment that will allow the appropriate tissue modeling and remodeling. The final phase is tissue turnover to allow reduction of the applied strain terminating 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
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 statistically significant (P ⬎.05) 1 day after giving the medicine or the reverse osmosis filtered water. However, 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. However, 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 regenerating 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 characteristics 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 observed between the control group and the acetaminophen group, the theory that acetaminophen does not inhibit periphereal secretion of PGs is supported, coinciding with the findings of Bianchi.22 CONCLUSIONS
1. Ibuprofen and aspirin significantly (P ⬍.01) reduced the numbers of resorption lacunae and osteoclasts in the pressure areas of orthodontic tooth movement, compared with the control and acetaminophen groups.
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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 2* 3† 4‡ 5 6 7 8 9 10
1.11 1.38 1.58 1.67 1.62 1.77 1.94 2.19 2.50 2.89
0.24 0.41 0.22 0.24 0.33 0.35 0.31 0.42 0.50 0.99
0.85 1.07 1.16 1.23 1.16 1.44 1.51 1.50 1.59 1.77
0.41 0.38 0.24 0.25 0.24 0.36 0.37 0.43 0.35 0.44
1.19 1.40 1.55 1.63 1.50 1.84 2.07 2.11 2.22 2.49
0.27 0.21 0.21 0.21 0.44 0.36 0.27 0.29 0.41 0.39
0.71 0.89 1.11 1.18 1.11 1.24 1.32 1.48 1.55 1.69
0.39 0.44 0.26 0.25 0.17 0.20 0.20 0.33 0.30 0.33
*P ⬍.031; †P ⬍.01; ‡P ⬍.0001.
7. Acetaminophen did not interfere with treatment in Wistar albino rats.
Fig 5. Radiographs of premaxillary suture in rat: A, before and B, after incisor separation.
2. Acetaminophen did not significantly (P ⬍.01) reduce the numbers of resorption lacunae and osteoclasts 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 acetaminophen 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 movement 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.
In this study, we analyzed the effects of nonsteroidal 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 hyperalgesia.32,33 The drugs that inhibit the liberation of PGs are a viable option to control pain after orthodontic treatment. As the number of adults having orthodontic treatment increases, the probability that they will take other medicines for long periods of time also increases— nonsteroidal anti-inflammatory drugs for arthritis, tricyclic 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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