ORIGINAL ARTICLE

M. V. Angelopoulou Pharmacological management of

V. Vlachou
pain during orthodontic treatment: a
D. J. Halazonetis
meta-analysis

Authors' affiliations: Angelopoulou M. V., Vlachou V., Halazonetis D.J. Pharmacological

M. V. Angelopoulou, Department of management of pain during orthodontic treatment: a meta-analysis
Paediatric Dentistry, School of Dentistry,
Orthod Craniofac Res 2012; 15: 71–83.  2012 John Wiley & Sons A ⁄ S
University of Athens, Athens, Greece
V. Vlachou, Private Dental Practice, Athens,
Greece Structured Abstract
D. J. Halazonetis, Department of
Objectives – To evaluate the effectiveness of non-steroidal anti-
Orthodontics, School of Dentistry,
University of Athens, Athens, Greece inflammatory drugs (NSAIDs) in managing pain arising from orthodontic
interventions, such as archwire or separators placement.
Correspondence to: Data Sources – Medline and Cochrane databases searched in February
Matina V. Angelopoulou
2010 and updated in July 2010 using orthodontics and pain as the search
Department of Paediatric Dentistry
School of Dentistry terms. Additional studies located from Google Scholar, Clinical Trials and
University of Athens the reference lists of retrieved articles.
2 Thivon Street Study Selection – Randomized controlled trials comparing NSAID to
Goudi 115 27, Greece
placebo using visual analogue scale (VAS) scores.
E-mail: [email protected]
Data Synthesis – Of the 1127 studies identified through database
searches, seven were included for meta-analysis. Treatment effects
(HedgesÕ g using random effects model) and 95% confidence intervals (CI)
of the pain VAS scores were evaluated at 2, 6 and 24 h after intervention,
during chewing and biting activities. Pain level at 2 h differed between the
ibuprofen and placebo groups during biting (95% CI: )0.178 to )0.046),
but not during chewing (95% CI: )0.551 to 0.148). At 6 h, the ibuprofen
group exhibited lower pain levels during both activities (chewing 95% CI:
)0.640 to )0.123, biting 95% CI: )0.857 to )0.172). At 24 h, no statistically
significant difference could be detected between ibuprofen and placebo
(chewing 95% CI: )0.642 to 0.112, biting 95% CI: )0.836 to 0.048). No
statistically significant difference was found between ibuprofen and
acetaminophen at any time point.
Conclusion – Ibuprofen appears to lower orthodontic pain compared to
placebo at 2 and 6 h after separators or archwire placement, but not at
24 h, when pain peaks.

Key words: analgesics; meta-analysis; orthodontics; pain

Date: Introduction
Accepted 13 February 2012

DOI: 10.1111/j.1601-6343.2012.01542.x Pain and discomfort are potential side effects of orthodontic
 2012 John Wiley & Sons A ⁄ S treatment (1–4), occurring in 91–95% of patients undergoing fixed
Angelopoulou et al. Meta-analysis of orthodontic pain management

orthodontic treatment (3, 5, 6); it may discourage contraindicated for pregnant and lactating
patients from treatment (7–9) or reduce their women, and for persons with nasal polypods,
compliance (10). angioedema and ocular reactions (13). Aspirin,
Pain has been reported after separator place- ibuprofen (35, 47) and indomethacine have been
ment (11–14), initial archwire placement (2, 3, 11, found to delay tooth movement (48). However, as
12, 15–18), headgear use (19), rapid palatal some studies indicated, low doses and specific
expansion (20) and chin cup therapy (21). Pain drugs, such as tenoxicam and acetaminophen, do
may also be induced during debonding (22) or not seem to interfere with tooth movement (33,
because of traumatic ulcers to the cheeks, lips or 34, 49). Acetaminophen reduces pain by inhibi-
tongue (5). No difference has been found in pain tion of cycloxogenase-3 in the brain and the
levels in patients treated with self-ligating, lingual spinal cord and by weak inhibition of peripheral
or conventional brackets (23–27). Higher pain prostaglandin synthesis (4, 34).
levels have been reported in the anterior region Although a multitude of studies has been pub-
than in the posterior (3, 11, 18) and in the lower lished on the topic of orthodontic pain manage-
rather than in the upper jaw (16). Concerning the ment, there seems to be lack of consensus con-
influence of gender on pain perception, some cerning the effectiveness of the suggested
studies report higher pain levels in females (3, 28), interventions. In recent years, orthodontic pain-
whereas other studies find no differences between related research seems to have reached adequate
genders (11, 15, 18, 23, 25, 27, 29, 30). Age may volume for performing a reliable meta-analysis.
also be a factor (3, 15, 16, 31), but findings are Xiaoting et al. (50) reported the results of such a
controversial (11, 23, 25, 27). study for drug interventions only. However, the
Pain during orthodontic treatment is related to results of their meta-analysis include all pain
changes in the periodontal ligament (PDL) that relief methods, do not include all the relevant
increase the number of multinuclear osteoclasts, studies and do not follow the PRISMA (preferred
promote osteoclastic bone resorption and thereby reporting items for systematic reviews and meta-
allow tooth movement (1, 26, 32–35). Orthodontic analyses) guidelines (51, 52).
force produces pressure to the PDL that leads to The aim of this study was to evaluate the
ischaemia, inflammation and oedema (36). As a effectiveness of pharmacological interventions on
result of inflammation, high levels of prostaglan- pain experienced by patients undergoing ortho-
dins, histamine, serotonine, bradykinin, substance dontic treatment, by reviewing randomized con-
P and cAMP are released to the PDL (12, 13, 33, 37– trolled trials (RCT) that report the efficacy of the
39). Pain may also be induced by pulp irritation most commonly used drugs (ibuprofen and acet-
during orthodontic tooth movement (40). aminophen) and to compare these two drugs to
Various methods have been proposed to man- each other and to placebo.
age orthodontic pain. The most commonly used is
the administration of non-steroidal anti-inflam-
matory drugs (NSAIDs), such as aspirin, acet- Methods
aminophen (paracetamol), ibuprofen, flurbipro-
fen, naproxen sodium and tenoxicam (4, 12–14, In the preparation of this meta-analysis, we fol-
34, 37, 41–44). Non-steroidal anti-inflammatory lowed the PRISMA (preferred reporting items for
drugs inhibit prostaglandin synthesis and reduce systematic reviews and meta-analyses) guidelines
inflammation to the PDL thus minimizing pain (51, 52). Methods of analysis, exclusion and
(12, 13, 42). However, NSAIDs may have side inclusion criteria and the main outcome measure
effects (14, 45, 46), such as gastric or duodenal [pain as evaluated on a visual analogue scale
ulceration, bleeding disorders, renal insufficiency, (VAS)], as well as the 24-h time point of pain
asthma, allergy, hypertension, congestive heart recording, were specified in advance of the study.
problems and atherosclerosis (43), even though The activity during which pain would be evalu-
their occurrence may be low (12). Ibuprofen is ated (e.g. biting, chewing, fitting teeth together,

72 Orthod Craniofac Res 2012;15:71–83

 Angelopoulou et al. Meta-analysis of orthodontic pain management

etc.) as well as additional time points of pain reference lists of the retrieved articles were sear-
recording was specified after the eligible studies ched to identify studies that might not have been
had been collected, based on study availability. included. The search term Ôorthodontics AND painÕ
The protocol was not published, nor was the study was used. Wild-card characters (e.g. Ôorthodont*Õ)
registered. did not produce additional records.
Randomized controlled trials evaluating phar- As a first step, the titles and abstracts of the
macological management of pain during ortho- articles were checked independently by two
dontic treatment were investigated. Trials were reviewers (MA, VV). If the reviewers could not
retrieved with no date, language or publication decide on a studyÕs eligibility by examining the
status restriction and limited to human subjects. title and the abstract, its full text was retrieved;
The exclusion criteria were the following: 1) trials any disagreements were resolved by discussion.
irrelevant to orthodontics; 2) studies concerning Duplicate studies were identified by comparing
orthodontics but irrelevant to pain; 3) articles authorsÕ names, title and results and removed
referring to temporomandibular joint disorders from the final count.
and orofacial pain; 4) studies referring to pain From each included study, we extracted the
because of oral surgery procedures, even if these studyÕs publication data (journal, title, authors,
were conducted for orthodontic reasons; 5) date), sample characteristics (sample size, gender,
authorÕs replies; 6) reviews; 7) articles presenting age), relevant results (VAS score, standard devia-
techniques to manage orthodontic pain; and 8) tion) and details of the intervention (time, drug
clinical trials reporting the amount of orthodontic type and dosage). The data were extracted by one
pain without management of this pain. author (MA) and checked by a second author
Inclusion criteria were as follows: 1) random- (DH). Disagreements were resolved by discussion
ized controlled trials comparing the efficacy of between the authors. Authors of six studies that
NSAIDs to placebo; 2) prospective studies; 3) use provided insufficient data for meta-analysis were
of a control group; 4) use of VAS to report pain contacted but only one responded and returned
levels; and 5) participants undergoing orthodontic the requested information. In two studies, the
treatment with fixed appliances, including sepa- results were presented as graphs only (12, 13). We
rator placement without age or gender restric- retrieved numerical values by measuring directly
tions. from the graphs, as the authors did not respond to
The main outcome was pain level during our query.
chewing and biting, as measured on a VAS, at 2, 6 Risk of bias was evaluated by considering spe-
and 24 h after orthodontic intervention. These cific criteria: 1) randomization method; 2) blind-
activities and the 24-h time point were chosen to ing; 3) report of drop-outs; 4) intention-to-treat
evaluate the effectiveness of NSAIDs at the peak of analysis; 5) selective reporting; and 6) incomplete
orthodontic pain (2, 3, 9, 11–13, 18, 19, 23, 25, 28, reporting. Each study was evaluated jointly by all
29, 42, 44). The 2- and 6-h time points, which have authors and consensus was reached.
been commonly assessed in the literature, were The data were analysed with the META-ANALYST
added for a more comprehensive evaluation. The statistical package (version 3.13, Tufts, Boston,
VAS system was considered a prerequisite, MA, USA). The standardized mean difference
because it has been found a reliable tool to eval- (SMD) and 95% confidence intervals (CI) of the
uate patientsÕ pain level, with good sensitivity and main outcome were estimated by the random
high reproducibility (3, 12, 17, 18, 29, 43). effects model, as proposed by DerSimonian and
Relevant studies were located by searching the Laird (53). HedgesÕ g was chosen as estimator of
Medline and Cochrane databases. The main the effect size. Heterogeneity was evaluated by I2.
search was conducted in February 2010 and Risk of bias across studies was evaluated by visual
updated in July 2010. We used Google Scholar and inspection of the funnel plot, and leave-one-out
Clinical Trials to retrieve additional studies analysis was performed to check the sensitivity of
(un-published reports and ongoing trials). The the results.

Orthod Craniofac Res 2012;15:71–83 73

Angelopoulou et al. Meta-analysis of orthodontic pain management

Results 43, 44), 400 mg ibuprofen (4, 12, 13, 30, 34, 43)
or 600 mg ibuprofen (44) and acetaminophen-
The electronic search produced 1127 articles paracetamol in various dosages (4, 34, 44) (Ta-
(Fig. 1). Application of the exclusion and inclusion ble 1). Three studies included groups receiving
criteria reduced these to 77 articles that were aspirin, naproxen sodium or flurbiprofen, but
evaluated in their full-text form. Of these, 14 these groups were not comparable to other
concerned the use of NSAIDs for orthodontic pain studies and were not included in the meta-
management, but only seven studies fulfilled all analysis (12, 43, 44). Time of administration
inclusion criteria, including the use of VAS scores differed between studies. In three studies, med-
and a control group, and these were used for the ication was given after orthodontic intervention
meta-analysis (Tables 1 and 2). (12, 13, 34), in one study medication was given
The finally selected studies were randomized before archwire application (43), and three trials
controlled clinical trials evaluating pain relief included both pre- and post-visit medication (4,
using NSAIDs during fixed orthodontic treatment. 30, 44).
Three studies evaluated pain after separator The Polat et al. (43) publication had errors in
placement (4, 13, 30), three studies after initial the results, but these were later corrected with an
archwire placement (34, 43, 44) and one study erratum. Because of high similarities of this
after both separator and archwire placement (12). study to another study (44), the leading author,
In six studies, pain was evaluated for 7 days (4, 12, common to both studies, was contacted to en-
13, 34, 43, 44), whereas one evaluated pain for the sure that the subjects did in fact differ between
first 24 h only (30). the two publications. Upon confirmation, we
The included studies involved a total of 621 retained both studies, in contrast to a previously
participants and had a mean age of participants published review (50). In the Bradley et al. (4)
between 13 to 18 years and various gender dis- study, discomfort was not differentiated between
tributions. The agents administered were lactose, chewing and biting, but a single VAS value was
as placebo, for the control group (12, 13, 30, 34, taken; we used this measurement for both
chewing and biting, considered the Ôday 1Õ value
as the 24-h measurement and used the Ôper-
Records identified through
protocolÕ values in the analysis. In the Salmas-
database searching
(n = 1127)
sian et al. (34) study, there was no discrimination
of discomfort between any activities; the mean
Records after duplicates Records excluded (n = 1052) VAS scores and standard deviations (SD) for the
removed
(n = 1126) Irrelevant to pain:
Irrelevant to orthodontics:
452
409
2- and 6-h time intervals were retrieved from the
TMJ-orofacial pain: 136
Pain due to surgical procedures: 55
3- and 7-h measurements. In the Minor et al.
Full-text articles assessed for
eligibillity
(n = 74)
(30) study, biting results were not published,
Additional records identified
whereas chewing results were the sum of pain
through reference lists
(n = 3) during chewing on both sides. In addition, this
study does not mention whether patients were
Full-text articles assessed for
eligibillity Full-text articles excluded (n = 70) excluded if additional medication was taken.
(n = 77)
Perception of pain: 38
Review or systematic review: 6 Two studies did not report mathematical data,
Technique presentation: 2
Author’s reply: 2 and their results were retrieved from graphs (12,
Non pharmacological intervention: 13
Non comparable pharmacological intervention: 7 13). In the study of Ngan et al. (12), no dis-
Non prospective trial: 1
Studies included in
qualitative synthesis
No control group: 1 crimination between pain levels of different
(n = 7)
activities could be obtained from the graphs.
Finally, Steen Law et al. (13) included patients
Studies included in
quantitative synthesis who took additional medication in the analysis;
(meta-analysis)
(n = 7) however, the authors mentioned that there was
Fig. 1. Flow chart of studies selection. no difference between groups regarding the

74 Orthod Craniofac Res 2012;15:71–83

 Table 1. Studies included in the meta-analysis (n: sample size, h: hours, d: days, ia: immediately after)

Gender Mean age Time pain Orthodontic Groups (sample size) and medications
Study n distribution (years) evaluated procedure administered

Ngan et al. 77 44% $ 16.6 ± 6.8 2, 6, 24 h Separators Group A (n = 23) 400 mg ibuprofen (ia)
(12) 56% # 2, 3, 7 d Archwire Group B (n = 28) 650 mg aspirin (ia)
Group C (n = 26) placebo (ia)

Steen Law 63 60% $ 13.4 ± 1.7 2, 6, 24 h Separators Group A (n = 22) 400 mg of ibuprofen (1 h before) ⁄ placebo (IA)
et al. (13) 40% # 13.3 ± 1.4 2, 3, 7 d Group B (n = 19) placebo (1 h before) ⁄ 400 mg of ibuprofen (IA)
13.1 ± 1.8 Group C (n = 22) placebo (1 h before) ⁄ placebo (IA)

Polat et al. (43) 60 38% $ 16.0 ± 6.1 2, 6 h Archwire Group A (n = 20) placebo (1 h before)
42% # 17.0 ± 7.0 At bedtime Group B (n = 20) 400 mg ibuprofen (1 h before)
15.0 ± 2.2 24 h, 3, 7 d Group C (n = 20) 550 mg naproxen sodium (1 h before)

Polat & 120 36% $ 16.0 ± 6.1 2, 6 h Archwire Group A (n = 20) placebo(1 h before) ⁄ placebo (6 h after)
Karaman (44) 64% # 15.0 ± 2.8 At bedtime Group B (n = 20) 600 mg ibuprofen (1 h before) ⁄ ibuprofen (6 h after)
15.0 ± 4.5 24 h Group C (n = 20) 100 mg flurbiprofen (1 h before) ⁄ flurbiprofen (6 h after)
16.0 ± 4.6 2, 3, 7 d Group D (n = 20) 500 mg acetaminophen (1 h before) ⁄ acetaminophen (6 h after)
15.0 ± 2.9 Group E (n = 20) 550 mg naproxen sodium (1 h before) ⁄ naproxen sodium
15.0 ± 3.7 (6 h after)
Group F (n = 20) 300 mg aspirin(1 h before) ⁄ aspirin (6 h after)

Bradley 159 64% $ 12–16 2, 6 h Separators Group A (n = 82) 400 mg ibuprofen (1 h before, 6 h after)
et al. (4) 36% # At bedtime Group B (n = 77) 1 g paracetamol (1 h before, 6 h after)
Next morning
2, 3, 7 d

Salmassian 60 48% $ 12–18 3, 7, 19, 24, Archwire Group A (n = 21) 600 mg acetaminophen (ia, 3, 7, 19, 24, 31, 48 h
et al. (34) 52% # 31, 48 h after, 3, 4, 7 d after)
3, 4, 7 d Group B (n = 19) 400 mg ibuprofen (ia, 3, 7, 19, 24, 31, 48 h after, 3, 4, 7 d after)
Group C (n = 20) placebo (ia, 3, 7, 19, 24, 31, 48 h after, 3, 4, 7 d after)

Minor et al. 52 58% $ 17.6 ± 5.0 2, 6 h Separators Group A (n = 16) 400 mg ibuprofen (1 h before) ⁄ 400 mg ibuprofen (3 h after) ⁄
(30) 42% # 14.9 ± 2.71 At bedtime 400 mg ibuprofen (7 h after)
6.4 ± 3.6 Next morning Group B (n = 17) placebo (1 h before) ⁄ 400 mg of ibuprofen (3 h after) ⁄

Orthod Craniofac Res 2012;15:71–83

24 h 400 mg ibuprofen (7 h after)
Group C (n = 18) placebo (1 h before) ⁄ placebo (3 h after) ⁄ placebo (7 h after)
Angelopoulou et al. Meta-analysis of orthodontic pain management

75
Angelopoulou et al. Meta-analysis of orthodontic pain management

Table 2. Quality measures of randomized clinical trials included in the meta-analysis

Placebo Patients Clinician Report of Per Selective

Study Randomization group blinded blinded drop-outs protocol reporting

Ngan et al. (12) Yes Yes Yes Yes Yes Yes Yes
Steen Law et al. (13) Yes Yes Yes Yes Yes No Yes
Polat et al. (43) Yes Yes Yes Yes Yes Yes No
Polat & Karaman (44) Yes Yes Yes Yes Yes Yes No
Bradley et al. (4) Yes No Yes Yes Yes Yes Yes
Salmassian et al. (34) Yes Yes Yes Yes Yes Yes No
Minor et al. (30) Yes Yes Yes Yes No Yes Yes

number of patients who took additional medi- analysis of the six studies comparing the effect of
cation. ibuprofen vs. placebo in pain levels during
Minor et al. (30) found that the group receiving chewing, 24 h after intervention, revealed no sta-
ibuprofen before and after separator placement tistically significant difference. The treatment ef-
experienced less pain (p < 0.05) at 6 h, at bedtime, fect (Tx effect) was )0.265 and the 95% confidence
and at awakening on the second day, but not at interval (CI) was )0.642 to 0.112 (Fig. 2). The re-
24 h. Steen Law et al. (13) also found lower levels sults did not differ when evaluating pain levels
of pain 2 h after intervention in the group during biting, using the same medications (ibu-
receiving preoperative ibuprofen, when compared profen vs. placebo) and time of measurement
to subjects who had taken preoperative placebo (24 h). Tx effect was )0.394 and 95% CI ranged
and post-operative ibuprofen, or the placebo from )0.836 to 0.048 (Fig. 3).
medication both preoperatively and post-opera- However, when comparing ibuprofen to pla-
tively, but there was no significant difference in cebo during chewing and biting at an earlier time
pain levels between groups at any of the sub- (6 h), we found a statistically significant effect. Tx
sequent post-operative times. Salmassian et al. effect for chewing was )0.381 and the 95% CI was
(34) found that acetaminophen, ibuprofen and )0.640 to )0.123 (Fig. 4), whereas the Tx effect for
placebo were equally effective at all time points. biting was )0.515 and the 95% CI was )0.857 to
Bradley et al. (4) found no statistically significant )0.172 (Fig. 5). At 2 h after intervention, pain
difference in pain scores between ibuprofen and levels between ibuprofen and placebo differed
paracetamol at 24 h. Polat et al. (43) did not find significantly during biting (Tx effect: )0.562, 95%
any significant differences between the placebo CI: )0.178 to )0.046, Fig. 6), but did not differ
and ibuprofen groups, while naproxen sodium significantly during chewing (Tx effect: )0.202,
(550 mg) taken 1 h before archwire placement 95% CI: )0.551 to 0.148, Fig. 7).
significantly decreased the severity of pain at 2, When comparing acetaminophen to ibuprofen,
6 h and at night-time. Polat and Karaman (44) no statistically significant differences were found
reported that patients receiving acetaminophen either for biting or for chewing, for any of the
had significantly less pain than those receiving three time points (2, 6 and 24 h).
placebo both at 6 and 24 h, while ibuprofen Significant evidence of heterogeneity between
proved better than placebo at 24 h after inter- studies was observed in biting, between placebo
vention. Finally, Ngan et al. (12) found that the and ibuprofen 2 h after intervention (Table 4,
placebo group had significantly more discomfort I2 = 69%, p < 0.05) and 24 h (I2 = 59%, p < 0.05),
than either the ibuprofen or the aspirin group at as well as in the acetaminophen vs. ibuprofen
all time points tested. measurements at 2 h (chewing, I2 = 71%, p < 0.05)
Detailed data for each study and meta-analysis and at 6 h (chewing, I2 = 68%, p < 0.05; biting, I2 =
results are presented in Tables 3 and 4. Meta- 80%, p < 0.05). Funnel plots confirmed evidence of

76 Orthod Craniofac Res 2012;15:71–83

 Angelopoulou et al. Meta-analysis of orthodontic pain management

Table 3. Mean visual analogue scale scores (cm on a 10-cm scale) and standard deviations (in parentheses) for studies included in the meta-analysis (n: sample size, h: hours)
asymmetry, perhaps signifying publication bias,

3.41 (2.33)**
1.31 (2.47)
2.64 (3.46)

3.59 (2.77)
although other factors cannot be excluded.
Leave-one-out analysis was conducted for the
24 h comparisons between ibuprofen and placebo

2.13 (2.94)
1.03 (1.51)
3.57 (2.21)
3.60 (2.73)
only, because of the small number of studies
comparing ibuprofen to acetaminophen. Remov-
6h

ing the Salmassian et al. (34) study caused the 2-h

chewing effect of ibuprofen to become signifi-

2.28 (2.65)
1.00 (2.01)
2.56 (2.04)
2.98 (2.66)
Acetaminophen

cantly different from placebo. In contrast,

removing any other study, except the Salmassian
2h

et al. (34) study, caused the 2-h biting effect to

20
20
80
21
revert to a non-significant difference. The 6-h data
n

were insensitive to study removal. The 24-h data

5.30 (1.31)
5.11 (3.12)
4.31 (3.12)
4.47 (2.97)
6.69 (2.84)
5.94 (3.12)
6.66 (2.96)

4.07 (2.75)
11.90 (4.67) for biting exceeded the significance limit by
removing the Steen Law et al. (13) study.
24 h

4.93 (1.21)
3.56 (2.77)
4.24 (3.07)
5.18 (3.07)
5.73 (3.71)
5.19 (3.31)
6.05 (3.27)

4.40 (2.50)
8.50 (5.52)

Discussion
6h

Overall, meta-analysis showed that ibuprofen is

4.61 (1.26)
2.55 (2.67)
2.68 (3.23)
3.92 (3.18)
5.41 (2.78)
3.81 (3.28)
3.91 (3.42)

2.51 (2.81)
4.80 (4.12)

more effective than placebo at 2 and 6 h, but it

has no statistically significant effect in reducing
2h
Placebo

pain 24 h after separators or archwire placement.

26
22
22
20
20
20
20

19
18

Acetaminophen was found to be equally effective

n

to ibuprofen at all time points and activities.

3.15 (2.27)*
4.60 (1.32)
5.30 (2.82)
4.56 (3.43)
5.46 (3.82)
6.08 (3.38)
2.45 (3.26)
2.62 (3.29)

3.63 (3.01)
10.30 (7.01)

These conclusions are based on a total of seven

randomized trials of similar design. Areas of non-
24 h

matching included time of intervention, dosage

and timing of drug administration, activity mea-
4.27 (1.44)
2.92 (2.37)
2.43 (2.62)
3.49 (3.04)
4.56 (3.50)
2.73 (3.18)
2.37 (3.08)
2.52 (2.14)
4.25 (2.71)
7.20 (5.36)

sured (chewing, biting) and orthodontic appliance

used (separators, archwire). It was not possible to
6h

select completely homogeneous studies, and

4.18 (1.18)
0.95 (1.21)
0.96 (1.06)
2.18 (2.68)
2.15 (2.44)
3.70 (2.75)
1.30 (2.07)
1.84 (1.89)
3.41 (2.61)
5.90 (5.77)

therefore, subgroup analysis was not performed.

In addition, some of the studies (12, 13) did not
Ibuprofen

2h

include numerical data, and the information was

retrieved from graphs, probably accompanied by
23
22
22
20
20
20
20
74
19
17
n

measurement error. Moreover, results may be

Chewing and biting
Sum of all activities

influenced by the difference in gender ratio of the

Chewing (sum of
Not specified

samples between studies. Another limitation

both sides)

stems from the small sample size (around 20

Chewing

Chewing

Chewing
Activity

Biting

Biting

Biting

subjects in each group) of most of the studies,

which reduces the confidence of the results and
may not allow detection of a true effect. Finally,
Salmassian et al. (34)
Polat & Karaman (44)
Steen Law et al. (13)

publication bias may have affected the results of

*n = 67, **n = 76.
Bradley et al. (4)

Minor et al. (30)

Ngan et al. (12)

Polat et al. (43)

the meta-analysis, because asymmetry was found

on some occasions between studies.
Sensitivity analysis of the results places more
Study

confidence on the 6- and 24-h conclusions. The

Orthod Craniofac Res 2012;15:71–83 77

Angelopoulou et al. Meta-analysis of orthodontic pain management

Table 4. Meta-analysis results: Standardized treatment effect (Tx effect), calculated as HedgesÕ g, 95% Confidence Interval (CI),
using random effects model and I2 values

Ibuprofen vs. Placebo (six studies) Ibuprofen vs. Acetaminophen (three studies)

Activity Time Tx effect 95% CI I2 Tx effect 95% CI I2

Chewing 2h )0.206 )0.550 to 0.138 0.456 0.049 )0.507 to 0.606 0.711*

6h )0.386 )0.638 to )0.133 0.000 )0.076 )0.600 to 0.447 0.679*
24 h )0.270 )0.642 to 0.102 0.532 )0.003 )0.266 to 0.261 0.000
Biting 2h )0.560 )1.065 to )0.056 0.691* )0.106 )0.488 to 0.276 0.421
6h )0.513 )0.847 to )0.179 0.313 0.054 )0.617 to 0.725 0.801*
24 h )0.395 )0.828 to 0.037 0.592* )0.072 )0.335 to 0.191 0.000

*p < 0.05.

Fig. 2. Forest plot for effect of

ibuprofen vs. placebo at 2 h (bit-
ing).

standardized effect size at 6 h was approximately magnitude of the effect under investigation. Esti-
)0.4 to )0.5, which translates to a reduction of mation of the appropriate sample size by a power
slightly <1.5 cm in the VAS. At 24 h, no statisti- analysis is important in clinical trials to assess the
cally significant treatment effect could be probability of Type II error. Investigators are
detected, but the confidence interval extended strongly encouraged to include such information.
towards the pain reduction direction, and, for the A possible explanation for the lack of efficacy of
biting activity, it reached the significance limit NSAIDs to control orthodontic pain at 24 h may
when removing one study. Therefore, it is con- be the inadequate dose of medication, because
ceivable that a small clinical effect may be pres- most of the times NSAIDs were taken many hours
ent, but the included studies may be too few or before the peak time of pain, but the peak plasma
contain samples too small to provide adequate concentration of ibuprofen is reached after 1–2 h
power to the meta-analysis for detection of this (30). This explains the positive effect of NSAIDs
effect. Statistical power is a testÕs ability to detect on orthodontic pain at 6 h. However, Salmassian
an effect, when one exists. Power is determined et al., (34) even with additional doses, did not find
by, among other factors, sample size and the any statistical significant differences between

78 Orthod Craniofac Res 2012;15:71–83

 Angelopoulou et al. Meta-analysis of orthodontic pain management

Fig. 3. Forest plot for effect of

ibuprofen vs. placebo at 2 h
(chewing).

Fig. 4. Forest plot for effect of

ibuprofen vs. placebo at 6 h (bit-
ing).

acetaminophen, ibuprofen or placebo. Thus, been produced (37). Thus, post-operative medi-
higher doses may be needed in addition to higher cation, arriving after inflammation has already
frequency of medication. Another explanation begun, may not abort the pain experience (13).
might be the differences in pain threshold and Preoperative use of acetaminophen (41) may
tolerance levels, because pain is subjective and prevent pain, because it reduces the formation
depends on factors such as patientÕs previous of prostaglandins and blocks afferent nerve
pain experiences, emotional state and cultural impulses before they reach the central nervous
background (30, 34, 44). Additionally, NSAIDs system (13, 42, 43). Preoperative, taken together
inhibit synthesis of prostaglandins, but are inca- with post-operative ibuprofen, was found to reduce
pable of stopping their action once they have pain, but pre- or post- only intervention did not

Orthod Craniofac Res 2012;15:71–83 79

Angelopoulou et al. Meta-analysis of orthodontic pain management

Fig. 5. Forest plot for effect of

ibuprofen vs. placebo at 6 h
(chewing).

Fig. 6. Forest plot for effect of

ibuprofen vs. placebo at 24 h (bit-
ing).

reduce pain adequately (42, 44). However, other NSAIDs in particular; 3) it analyses pain during
studies using preoperative and post-operative biting and chewing separately. The last point
medication did not report pain relief at peak pain makes direct comparison of the results between
time (4, 30). the two meta-analyses difficult because the Xia-
This study appears after the meta-analysis of oting et al. (50) study does not specify which
Xiaoting et al. (50) on orthodontic pain. The activity was used for analysis.
present study differs in that: 1) it follows the The clinically relevant question is whether we
PRISMA guidelines (51, 52), proposed as the most should prescribe medication for management of
valid methodology for meta-analyses; 2) it focuses orthodontic pain in view of the potential side
on pharmacological management of pain, and effects on our young patients. There is no easy

80 Orthod Craniofac Res 2012;15:71–83

 Angelopoulou et al. Meta-analysis of orthodontic pain management

Fig. 7. Forest plot for effect of

ibuprofen vs. placebo at 24 h
(chewing).

answer and each clinician should weigh general served at 24 h, when pain is most intense. 3) The
and patient-specific factors for a final decision. frequency of pain experiences. Orthodontic
Patient-specific factors are mainly related to treatment requires regular appointments every
each patientÕs sensitivity and past pain experi- few weeks for archwire adjustments. If pain
ences, but also to dental status and to treatment management is justified for the first appoint-
specifics. No research is available in this area. ment, then it seems that it would be required at
General factors include the following: 1) the every subsequent appointment as well. This is
estimated treatment effect. The results of this usually not followed, and there are no data to
meta-analysis show an average treatment effect show if pain diminishes during the course of
of approximately 1.5 cm on the visual analogue treatment, if patients learn to accept it, or if
pain scale at 6 h. This reduction has to be orthodontists assume it is not an important issue
evaluated in comparison with the overall range anymore.
of pain values reported. Although this differed The trials evaluated here used a placebo group
greatly between studies, it was surprising to note for comparison. This is considered essential be-
that some very high values were recorded (the cause—stated perhaps too simplistically—it
mean values and standard deviations reported in establishes the minimum pain level that can be
Table 3 can be used to infer the range of VAS achieved by suggestive means; any further
scores). This seems contrary to the general belief reduction is considered purely pharmacological.
that orthodontic pain is minimal for most However, the patients who took part in these
patients. It is not clear in some studies how the studies were not experiencing any pain when re-
extremes of the VAS line were described to the cruited, or when receiving pre-treatment medi-
patients, but the customary Ôworst pain imagin- cation. It is conceivable that, merely the sugges-
ableÕ for the extreme right of the line was tion that orthodontic intervention might cause
probably not followed, either by the investigators pain requiring analgesics, would increase pa-
or the patients, or, the patients were lucky en- tientsÕ expectation of pain and thus pain itself. No
ough to not have experienced worse pain before. data are available as to the level of pain produced
In any case, a 1.5-cm effect (on a scale of 10) by orthodontic intervention when no medication
seems moderate to low. 2) The timing of the is given and when any inquiries about such pain
treatment effect. Although pain was reduced at are just dismissed by the orthodontist as un-
6 h, no statistically significant effect was ob- founded.

Orthod Craniofac Res 2012;15:71–83 81

Angelopoulou et al. Meta-analysis of orthodontic pain management

Conclusions inflammatory drugs (NSAIDs) is advocated but

effectiveness is debatable. This meta-analysis
Ibuprofen can reduce pain at 6 h after orthodon- shows that pain is reduced at 2 and 6 h after
tic procedure, whereas it has a statistically non- orthodontic intervention, but no significant effect
significant effect at 24 h, the peak pain time, after is present at 24 h, when pain reaches its maxi-
separators or archwire placement. There seems mum value. Ibuprofen and acetaminophen seem
to be no difference in effectiveness between equally effective, although the evidence is weak.
ibuprofen and acetaminophen, although the evi- The transient effect of NSAIDs and the moderate
dence is weak. pain reduction they achieve may not justify
analgesic prescription, at least according to the
dosage scheme used in the reviewed studies.
Clinical relevance
Acknowledgements: We wish to thank the authors of
the papers that responded to our queries and
Pain has been reported as a common side effect
provided clarifications and additional data for the
during orthodontic treatment. Pharmacological meta-analysis.
management of pain using non-steroidal anti-

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