Effectiveness of acetaminophen in comparison with ibuprofen for pain control in orthodontic patients: A systematic review and meta-analysis

Abstract

Objective

To compare the effectiveness of acetaminophen and ibuprofen for pain control in orthodontic patients.

Methods

Using the PICO strategy, studies were included without restrictions on publication date or language. PubMed, EMBASE, Scopus, Virtual Health Library (VHL)/Latin American and Caribbean Health Sciences Literature (LILACS), Web of Science, and Cochrane Library databases were searched, along with gray literature, up to July 2025. The methodological quality of the studies was assessed using the Cochrane Risk of Bias 2 tool. A meta-analysis was conducted using R software. Subgroup and leave-one-out sensitivity analyses were conducted for moderate or high heterogeneity.

Results

Of the 1,139 studies identified, 13 were included. The ages of the participants ranged from 9 to 30 years. Most studies (n = 7) were double-blinded. Tooth movement was induced by fixed appliances or separators, and two studies had a high risk of bias. Pain control with the two medications showed no significant differences at rest at 24 and 48 hours or during chewing at 6, 24, and 48 hours (P > 0.05). Heterogeneity was low, except for pain during chewing at 24 hours (I² = 68.7%; τ² = 1.24; P = 0.022) for this outcome, the “before” subgroup showed no heterogeneity, while the “before/after” subgroup showed high heterogeneity (I² = 84.3%; τ² = 3.38; P = 0.012). The leave-one-out analysis did not change the combined effect but indicated one study as a source of heterogeneity.

Conclusions

Pain control during orthodontic tooth movement did not differ between the two medications.

INTRODUCTION

Tooth movement occurs through the application of orthodontic forces, which displace the tooth within the periodontal ligament and create compression and tension zones. This mechanical stimulus initiates an inflammatory response that is essential for alveolar bone remodeling and also activates nerve endings, triggering neurogenic inflammation.¹ Consequently, tooth movement is inherently associated with pain from both peripheral nerve stimulation and the inflammatory process.^2,3

Orthodontic pain may be the most important adverse effect of treatment and is a major barrier to patient adherence. It is associated with missed appointments, reduced satisfaction with treatment outcomes, impaired oral hygiene, dietary changes, and even premature treatment discontinuation.^3-5 Several methods have been proposed to manage orthodontic pain, including non-pharmacological and pharmacological approaches. Among these, acetaminophen and non-steroidal anti-inflammatory drugs (NSAIDs) have attracted particular attention, with ibuprofen being one of the most commonly used and extensively studied.^3,6,7

Acetaminophen and ibuprofen have distinct mechanisms of action. Ibuprofen is an NSAID that inhibits peripheral cyclooxygenase to reduce the production of prostaglandin, which mediates inflammation and pain during tooth movement. Thus, it provides analgesia and local anti-inflammatory effects that may affect orthodontic tooth movement. In contrast, acetaminophen is a non-opioid analgesic with central action and minimal anti-inflammatory effects.^8-11 Some studies have suggested that ibuprofen may alter the rate of tooth movement, while acetaminophen does not appear to have this effect.^10,12

Despite the available literature on the efficacy, mechanisms of action, and potential side effects of both medications, clinical orthodontists still lack high-quality scientific evidence to support decision-making regarding their prescription. Therefore, the aim of this systematic review and subsequent meta-analysis was to compare the effectiveness of acetaminophen and ibuprofen in controlling pain in orthodontic patients.

MATERIALS AND METHODS

Protocol and registration

This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist¹³ and was registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42024138297).

Study design and eligibility criteria

This systematic review was based on the following research question: “Is acetaminophen more effective than ibuprofen in controlling pain in patients undergoing orthodontic treatment?” To address this question, the PICO framework was applied, where P = patients undergoing orthodontic tooth movement, I = use of acetaminophen for pain control during orthodontic tooth movement, C = use of ibuprofen for pain control during orthodontic tooth movement, and O = pain resulting from orthodontic tooth movement.

The following inclusion criteria were applied: randomized or non-randomized clinical trials that evaluated the effectiveness of acetaminophen in comparison with ibuprofen in controlling pain in patients undergoing orthodontic tooth movement, regardless of the presence of other comparison or placebo groups. Studies were included if they assessed pain as a primary or secondary outcome using a visual analog scale (VAS) in patients of any sex or age who underwent orthodontic tooth movements induced by separators, coil springs, fixed orthodontic appliances, or aligners. No restrictions were applied regarding language or year of publication.

The exclusion criteria were as follows: editorials, commentaries, opinion articles, guidelines, pilot studies, reviews of any type, in vitro and ex vivo studies, animal studies, observational and descriptive studies, case reports, and case series. Studies involving patients undergoing treatment with orthopedic appliances, those in which acetaminophen and/or ibuprofen were used exclusively in combination with other drugs, and those that did not use the VAS for pain assessment were also excluded.

Information sources and search strategy

The literature search was conducted using the following electronic databases: MEDLINE via PubMed, EMBASE, Scopus, Virtual Health Library (VHL)/Latin American and Caribbean Health Sciences Literature (LILACS), Web of Science, and Cochrane Library. In addition, a complementary search of gray literature was carried out by Connecting REpositories (CORE), Bielefeld Academic Search Engine (BASE), and Google Scholar. Up to the first 100 records retrieved from each gray literature source were included.¹⁴

To identify unpublished and ongoing clinical trials relevant to the review question, searches were conducted across the following trial registries: International Standard Randomised Controlled Trial Number, International Clinical Trials Registry Platform, ClinicalTrials.gov, Brazilian Registry of Clinical Trials, and EU Clinical Trials Register.

The search strategy was adapted for each database using Medical Subject Headings and Health Sciences Descriptors, with terms combined using the Boolean operators “AND” and “OR.” The searches were conducted in October 2024 and updated in July 2025.

The reference lists of the included studies were manually screened to identify relevant publications. Reference management was performed using Rayyan software (Rayyan Systems Inc., Cambridge, MA, USA).

Study selection and data extraction

The study selection was performed in two phases. First, titles and abstracts were independently screened by two reviewers (NMN and ÁOLJR) on the basis of predefined eligibility criteria, and disagreements were resolved by a third reviewer (FT). In the second phase, the full texts of potentially eligible studies were independently assessed by the same reviewers, and disagreements were resolved by consensus or, if needed, by a third reviewer.

A customized data-extraction form was used to collect key information from the included studies, including data pertaining to the first author, year, country, recruitment setting, sample size, participants’ sex and age, appliances used to induce tooth movement, randomization, blinding, medication concentration, administration protocol, and activity and time points of pain assessment.

Risk-of-bias assessment

Methodological quality was assessed using the Cochrane Risk of Bias 2 (RoB 2) tool,¹⁵ which evaluates five domains: (1) randomization process, (2) deviations from intended interventions, (3) missing outcome data, (4) outcome measurement, and (5) selection of reported results. Each domain included signaling questions answered as “yes,” “probably yes,” “probably no,” “no,” or “no information.”

Overall risk-of-bias judgments were classified as “low risk” if all domains were low risk; “some concerns” if at least one domain raised concerns but none were high risk; and “high risk” if one or more domains were high risk or multiple domains raised concerns that significantly lowered confidence. Two reviewers (NMN and ÁOLJR) independently applied the tool, and disagreements were resolved by a third reviewer (IGPOA).

The Risk-of-Bias VISualization tool was used to graphically represent the risk-of-bias assessments of the included studies.¹⁶

Meta-analysis

A meta-analysis of continuous data was performed using R 2024.12.1 (R Core Team, Vienna, Austria). Studies with comparable outcomes regarding the activity and time points of pain assessment were included, namely, rest_24h, rest_48h, chewing_6h, chewing_24h, and chewing_48h. The mean difference (MD) between the groups and the corresponding 95% confidence intervals (CIs) were calculated.

The meta-analysis was conducted using a random-effects model, as described by DerSimonian and Laird.¹⁷ Heterogeneity among studies was assessed using the I² statistic and Cochran’s Q test. I² values ≥ 50% were interpreted as indicative of substantial heterogeneity.¹⁸ For meta-analyses including more than two studies with I² > 40% and those showing potential methodological differences, sensitivity analyses were performed. Accordingly, a subgroup analysis was conducted to investigate the influence of the medication administration protocol: before or before and after the procedure. Additionally, a leave-one-out analysis was performed to assess the influence of each study on effect size and heterogeneity. For this purpose, each study was systematically removed one at a time and the overall effect size estimate was recalculated after each exclusion.

Certainty of evidence

The certainty of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Evidence from randomized clinical trials was initially rated as high and then downgraded based on the risk of bias, inconsistency, indirectness, and imprecision. Overall certainty was classified as high, moderate, low, or very low, and outcome importance was defined a priori. GRADE evidence profiles and tables summarizing the findings were generated using GRADEpro GDT (Evidence Prime Inc., Hamilton, ON, Canada).

RESULTS

A total of 1,139 records were identified, including 930 from databases and 209 from clinical trial registries. After removing duplicates, 830 records remained (Figure 1). After screening of titles and abstracts, 17 full-text articles were sought for retrieval; of these, two were unavailable. Finally, 15 articles were assessed for eligibility. After applying the eligibility criteria, two studies^8,19 were excluded, resulting in 13 studies being included in the systematic review.^7,11,20-30 The main characteristics and summary data of these studies are presented in Tables 1 and 2.^7,11,20-30

Figure 1.

Flowchart of the study methodology. Adapted from PRISMA 2020.¹³

VAS, visual analog scale.

Table 1.

Characteristics of the included studies (n = 13)

Study	Country	n	Sex (male)	Age (yr)	Device	Blinding	Activities in which pain was assessed	Pain assessment time points
Abdaljawwad and Al-Groosh (2022)11	Iraq	40	NR	21.13 ± 1.81 [18–24]	Fixed appliance	Double-blind	Fitting the front teeth; fitting the back teeth; chewing	Before; 0 hr; 1 day; 2 days; 3 days
Bird et al. (2007)20	USA	33	NR	[9–19]	Separator	Double-blind	Rest; fitting the back teeth; chewing	Before; 0 hr; 2 hr to 3 hr; bedtime; next day
Bradley et al. (2007)21	United Kingdom	159	57	NR	Separator	Triple-blind	Biting/chewing	2 hr; 6 hr; bedtime; next day; 2 days; 3 days; 7 days
Keith and Bollen (2019)22	USA	22	10	23.1 ± 14.3	NR	Triple-blind	Rest; light biting; chewing paraffin	0 hr; 6 hr; 1 day; 2 days
Hosseinzadeh Nik et al. (2016)23	Iran	89	NR	NR	Separator	Triple-blind	Biting/chewing	0 hr; 2 hr; 6 hr; bedtime; 1 day
Ousehal et al. (2009)24	Morocco	56	17	NR	Fixed appliance	NR	NR	2 hr; 6 hr; 1 day; 2 days; 3 days; 7 days
Patel et al. (2011)25	USA	24	13	26.4 ± 2.5 [19–30]	Separator	Double-blind	Fitting the front teeth; fitting the back teeth; biting; chewing	2 hr; 6 hr; bedtime; on waking; 1 day
Polat and Karaman (2005)26	Türkiye	120	76	NR	Fixed appliance	Double-blind	Fitting the front teeth; fitting the back teeth; biting; chewing	2 hr; 6 hr; bedtime; 1 day; 2 days; 3 days; 7 days
Salmassian et al. (2009)27	USA	60	31	[12–18]	Fixed appliance	Double-blind	Not considered	Before; 3 hr; 7 hr; 19 hr; 1 day; 31 hr; 48 hr; 3 days; 4 days; 7 days
da Silva Santos and Capelli Jr. (2021)7	Brazil	81	37	NR	Fixed appliance	Single-blind	Rest; biting	2 hr; 1 day; 2 days; 3 days; 7 days; 21 days
Sudhakar et al. (2014)28	India	138	66	[15–21]	Separator	Double-blind	Rest; fitting the back teeth; chewing	2 hr; 6 hr; bedtime; next morning; 2 days; 3 days; 7 days
Tunçer et al. (2014)29	Türkiye	45	14	14.5 ± 2.0 [10.8–20.5]	Fixed appliance	Double-blind	Fitting the front teeth; fitting the back teeth; chewing	Before; 0 hr; 1 day; 2 days; 3 days; 7 days
Zarif Najafi et al. (2015)30	Iran/USA	241	60	NR	Separator	Triple-blind	Rest; fitting the back teeth; chewing	0 hr; 2 hr; 6 hr; 1 day; 2 days

Values are presented as number only or mean ± standard deviation [min–max].

NR, not reported.

Table 2.

Characteristics of studies on the evaluated medications (n = 13)

Study	Acetaminophen concentration (mg)	Ibuprofen concentration (mg)	Administration protocol
Abdaljawwad and Al-Groosh (2022)11	500	400	1 tablet, 3 times/day for 3 days
Bird et al. (2007)20	650	400	1 tablet, 1 hr before
Bradley et al. (2007)21	500	200	2 tablets, 1 hr before and 6 hr after the initial dose
Keith and Bollen (2019)22	650	400	1 tablet before the orthodontic intervention
Hosseinzadeh Nik et al. (2016)23	650	400	1 tablet 1 hr before and every 6 hr up to 24 hr
Ousehal et al. (2009)24	500	300	1 tablet, 4 times/day for 7 days/ 2 times/day for 5 days
Patel et al. (2011)25	650	400	1 tablet 1 hr before, 3 hr after and 7 hr after
Polat and Karaman (2005)26	500	400	1 tablet, 1 hr before and 6 hr after
Salmassian et al. (2009)27	600	400	2 tablets, 3 hr, 7 hr, 19 hr, 24 hr, 31 hr, 48 hr, 3 days, 4 days and 7 days after
da Silva Santos and Capelli Jr. (2021)7	500	400	1 tablet, after the orthodontic intervention and every 6 hr for 1 week
Sudhakar et al. (2014)28	650	400	1 tablet, 1 hr before and 6 hr after
Tunçer et al. (2014)29	500	400	1 tablet, 1 hr before and 6 hr after
Zarif Najafi et al. (2015)30	650	400	1 tablet, 1 hr before

Qualitative synthesis

The studies were conducted in a range of countries, namely, the United States of America,^{20,22,25,27,30} Türkiye,^26,29 Iran,^23,30 Iraq,¹¹ United Kingdom,²¹ Morocco,²⁴ Brazil,⁷ and India²⁸. Participant recruitment was performed across universities,^{7,11,20,22,23,25-30} hospitals,^21,24 and private clinics.¹¹ The sample size ranged from 22²² to 241³⁰ participants. All studies included patients of both sexes.^7,11,20-30 The minimum reported age was 9 years,²⁰ and the maximum was 30 years²⁵.

Orthodontic tooth movement was induced using fixed appliances^{7,11,24,26,27,29} or separators.^{20,21,23,25,28,30} The study by Keith and Bollen²² did not report the method used.

All included studies were randomized clinical trials.^7,11,20-30 Most of them (n = 7) were double-blind,^11,20,25-29 while four were triple-blind.^21-23,30 The study by da Silva Santos and Capelli Jr.⁷ was single-blind, and Ousehal et al.²⁴ did not report any information regarding blinding (Table 1).

The included studies demonstrated substantial heterogeneity in the activities and time points used for pain assessments. Pain was evaluated at rest in five studies,^{7,20,22,28,30} during chewing in ten,^{11,20-23,25,26,28-30} while biting in five,^{7,21,23,25,26} while fitting the front teeth in five,^{7,25,26,29,30} and while fitting the posterior teeth in seven.^{11,20,25,26,28-30} Salmassian et al.²⁷ did not specify the activity performed during pain assessment, and Ousehal et al.²⁴ did not report any information on this aspect. The time points for pain assessment also varied, ranging from immediately before (n = 4)^7,20,27,29 up to 21 days after the application of orthodontic force (n = 1).⁷ The number of assessment time points ranged from four²² to ten²⁷ (Table 1).

The concentrations of acetaminophen used in the included studies were as follows: 500 mg (n = 6),^{7,11,21,24,26,29} 600 mg (n = 1),²⁷ and 650 mg (n = 6).^{20,22,23,25,28,30} The concentrations of ibuprofen were 200 mg (n = 1),²¹ 300 mg (n = 1),²⁴ and 400 mg (n = 11)^{7,11,20,22,23,25-30} (Table 2).

The medication administration protocols varied considerably. In most studies (n = 9), the drug was administered up to 1 hour before the procedure,^{20-23,25,26,28-30} while in one study, administration occurred immediately after the procedure.⁷ In the majority of studies (n = 10), additional doses were administered after the procedure,^{7,11,21,23-29} following different protocols: three times daily for 3 days (n = 1);¹¹ 6 hours after the initial dose (n = 4);^21,26,28,29 every 6 hours for 24 hours (n = 1);²³ four times daily for 7 days for acetaminophen and twice daily for 5 days for ibuprofen (n = 1);²⁴ at 3 and 7 hours after the procedure (n = 1);²⁵ at 3 hours, 7 hours, 19 hours, 24 hours, 31 hours, and 48 hours and 3 days, 4 days, and 7 days after the procedure (n = 1)²⁷ and every 6 hours for 1 week if pain persisted (n = 1)⁷ (Table 2).

Abdaljawwad and Al-Groosh,¹¹ Bradley et al.,²¹ Sudhakar et al.,²⁸ and Tunçer et al.²⁹ reported that ibuprofen was more effective than acetaminophen in controlling orthodontic pain. Keith and Bollen²² and Polat and Karaman²⁶ reported better outcomes with acetaminophen treatment. da Silva Santos and Capelli Jr.,⁷ Bird et al.,²⁰ Hosseinzadeh Nik et al.,²³ Ousehal et al.,²⁴ and Salmassian et al.²⁷ found no significant differences between the two medications.

Risk-of-bias assessment

The results of the risk-of-bias assessment are shown in Figure 2. Most studies were rated as having “some concerns” in domain 2 (n = 11)^{11,20-23,25-30} and domain 5 (n = 12).^11,20-30 One study was rated as “high risk” in domain 3,²² while another study was rated as “high risk” in domains 2, 3, and 4.²⁴ The study by da Silva Santos and Capelli Jr.⁷ received a “low risk” rating across all domains. In the overall judgment, 10 studies^{11,20,21,23,25-30} were classified as having “some concerns,” two^22,24 as having “high risk of bias,” and one⁷ as having “low risk of bias.”

Figure 2.

Risk-of-bias assessment (n = 13).

Meta-analysis

No statistically significant difference (P > 0.05) was observed between the medications at rest at 24 hours and 48 hours, as well as in the overall effect estimate. Heterogeneity was 0% at both time points (Figure 3).

Figure 3.

Meta-analyses of mean pain differences between groups treated with acetaminophen and ibuprofen. A, Outcomes for rest_24h. B, Outcomes for rest_48h.

SD, standard deviation; MD, mean difference; CI, confidence interval.

For chewing activity, no statistically significant differences (P > 0.05) were found between the medications at 6, 24, and 48 hours, as well as in the overall effect estimate (Figure 4). The I² was 10.2% at 6 hours (MD = −0.25; 95% CI: −1.09 to 0.59) and 0% at 48 hours (MD = −0.69; 95% CI: −1.44 to 0.06) (Figure 4A and 4C). In contrast, heterogeneity for chewing at 24 hours was high (I² = 68.7%; τ² = 1.24; P = 0.022) (Figure 4B). For this outcome, a subgroup analysis based on medication protocol showed no heterogeneity in the “before” group (I² = 0%; τ² = 0; P = 0.087), whereas the “before and after” group showed high heterogeneity (I² = 84.3%; τ² = 3.38; P = 0.012). The test for subgroup differences did not indicate a significant difference between protocols (χ² = 0.34; P = 0.558) (Figure 5).

Figure 4.

Meta-analyses of mean pain differences between groups treated with acetaminophen and ibuprofen. A, Outcomes for chewing_6h. B, Outcomes for chewing_24h. C, Outcomes for chewing_48h.

SD, standard deviation; MD, mean difference; CI, confidence interval.

Figure 5.

Meta-analyses of mean pain differences by medication protocol subgroup (before, before/after) for the outcome “chewing_24h.”

SD, standard deviation; MD, mean difference; CI, confidence interval.

The leave-one-out analysis revealed that excluding the study by Tunçer et al.²⁹ reduced heterogeneity to a low level, but had no influence on the statistical significance of the effect estimate (Table 3).^22,26,29,30

Table 3.

Leave-one-out analysis for the outcome “chewing_24h”

Removed study	MD	95% CI	P value	τ²	τ	I² (%)
Keith and Bollen (2019)22	0.05	–1.62 to 1.72	0.954	1.70	1.30	79
Polat and Karaman (2005)26	0.36	–1.25 to 1.98	0.659	1.34	1.16	73.7
Tunçer et al. (2014)29	–0.66	–1.49 to 0.17	0.121	0	0	0
Zarif Najafi et al. (2015)30	0.23	–1.68 to 2.15	0.810	1.87	1.37	70.6
Pooled estimate	0.01	–1.36 to 1.38	0.989	1.24	1.11	68.7

MD, mean difference; CI, confidence interval; τ², between-study variance; τ, square root of τ² (standard deviation of true effect sizes); I², percentage of total variation across studies due to heterogeneity.

Certainty of evidence

The certainty of evidence was assessed for the five pain-related outcomes. With the GRADE approach, certainty was moderate for most outcomes and very low for pain during chewing at 24 hours owing to the risk of bias, inconsistency, and imprecision. Outcome importance was classified as critical or important, and detailed GRADE evidence profiles and Summary of Findings tables are presented (Table 4).

Table 4.

GRADE summary of findings for acetaminophen compared with ibuprofen for pain control during orthodontic tooth movement

Certainty assessment								No. of patients			Effect		Certainty	Importance
No. of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations		Acetaminophen	Ibuprofen		Relative(95% CI)	Absolute (95% CI)
Pain at rest 24 hours (follow-up: 24 hours; assessed with: VAS; Scale from: 0 to 10)
3	Randomized trials	Seriousa	Not serious	Not serious	Not seriousb	None		102	104		-	MD 0.11 higher(0.38 lower to 0.6 higher)	⊕⊕⊕◯ Moderatea,b	Critical
Pain at rest 48 hours (follow-up: 48 hours; assessed with: VAS; Scale from: 0 to 10)
3	Randomized trials	Seriousa	Not serious	Not serious	Not seriousb	None		102	104		-	MD 0.48 lower(1.12 lower to 0.17 higher)	⊕⊕⊕◯ Moderatea,b	Critical
Pain during chewing 6 hours (follow-up: 6 hours; assessed with: VAS; Scale from: 0 to 10)
3	Randomized trials	Seriousa	Not serious	Not serious	Not seriousb	None		103	104		-	MD 0.25 lower(1.09 lower to 0.59 higher)	⊕⊕⊕◯ Moderatea,b	Important
Pain during chewing 24 hours (follow-up: 24 hours; assessed with: VAS; Scale from: 0 to 10)
4	Randomized trials	Seriousa	Seriousc	Not serious	Seriousb	None		118	119		-	MD 0.69 lower(1.44 lower to 0.05 higher)	⊕◯◯◯ Very lowa,b,c	Critical
Pain during chewing 48 hours (follow-up: 48 hours; assessed with: VAS; Scale from: 0 to 10)
4	Randomized trials	Seriousa	Not serious	Not serious	Not seriousb	None		118	119		-	MD 0.01 higher(1.36 lower to 1.38 higher)	⊕⊕⊕◯ Moderatea,b	Critical

Certainty of evidence was graded as high (⊕⊕⊕⊕), moderate (⊕⊕⊕◯), low (⊕⊕◯◯), or very low (⊕◯◯◯) according to the GRADE approach. ⊕ indicates one retained level of certainty, and ◯ indicates one downgraded or unretained level.

CI, confidence interval; GRADE, Grading of Recommendations Assessment, Development and Evaluation; MD, mean difference; RoB 2, revised Cochrane risk-of-bias tool for randomized trials; VAS, visual analog scale.

^aMost included randomized trials were judged as having some concerns regarding risk of bias, mainly related to deviations from intended interventions and selective reporting, according to the RoB 2 tool. Although no consistent high risk of bias was identified across studies, these concerns reduced confidence in the estimate.

^bImprecision was rated as serious only for pain during chewing at 24 hours, as the confidence interval included values compatible with both no effect and a potentially clinically important benefit. For all other outcomes, confidence intervals were sufficiently narrow and remained within a clinically unimportant range, despite crossing the null effect, and therefore were not judged to warrant downgrading for imprecision.

^cSubstantial statistical heterogeneity was observed (I² = 68.7%; τ² = 1.24; P = 0.022), indicating important variability across studies. Although subgroup and sensitivity analyses suggested that differences in medication administration protocols may explain part of the heterogeneity, inconsistency remained relevant.

DISCUSSION

This systematic review and meta-analysis aimed to evaluate the effectiveness of acetaminophen in comparison with ibuprofen for pain control among orthodontic patients. These results indicated no significant difference between the two medications. The analgesic efficacy was similar at 24 and 48 hours at rest^7,22,30 and during mastication at 6,^22,26,30 24, and 48 hours.^22,26,29,30 These findings are consistent with the results of the studies by Bird et al.,²⁰ Ousehal et al.,²⁴ Salmassian et al.,²⁷ Hosseinzadeh Nik et al.,²³ and da Silva Santos and Capelli Jr.,⁷ which reported no significant differences between the medications. Previous systematic reviews have also shown no significant differences between the two drugs.^3,6,9,31,32 Sandhu et al.,³³ on the other hand, concluded that NSAIDs produce superior results.

In terms of methodological quality, most studies^{11,20,21,23,25-30} were rated as having “some concerns” regarding the risk of bias, particularly in domains related to deviations from intended interventions (domain 2) and the selection of reported outcomes (domain 5). Two studies^22,24 were classified as having “high risk of bias.” These results highlight the need for future clinical trials with greater methodological rigor and clearer descriptions of the interventions.

The low heterogeneity among the analyzed studies strengthened the reliability of the results, with the exception of the “chewing_24h” outcome, which showed high heterogeneity. Subgroup and leave-one-out sensitivity analyses indicated that the heterogeneity in this outcome was mainly associated with differences in medication administration protocols (before and after the procedure) and the inclusion of the study by Tunçer et al.²⁹

The included studies demonstrated considerable methodological heterogeneity in terms of medication concentrations and administration protocols (number of tablets, dosing intervals, and duration of use). Some studies initiated medication administration before the orthodontic procedure,^{20-23,25,26,28-30} while others began administration afterward.^7,11,27,30 The duration of medication use ranged from one^{20-23,25,26,28-30} to 7 days.^7,24,27 Additionally, substantial variability was noted in the methods used to induce tooth movement, the activities performed by patients during pain assessment, and the timing of pain measurements. This heterogeneity complicated the standardization of results and should be carefully considered when translating these findings into clinical practice.

According to the GRADE evaluation, the certainty of evidence was moderate for most outcomes, mainly due to the risk of bias, but was very low for pain during chewing at 24 hours because of the risk of bias, inconsistency, and imprecision. Although the evidence indicated no clinically meaningful difference between acetaminophen and ibuprofen, the findings should be interpreted with caution, and further well-designed randomized trials are needed to improve certainty.

Future studies should aim to standardize pain assessment at key time points: immediately before the procedure, immediately after the procedure, and at 24 and 48 hours post-procedure, when pain intensity typically peaks.^7,26,27 Regarding the activities evaluated, pain assessment should be performed during the most representative daily activities of patients, such as resting and chewing. The use of the VAS is recommended, since it is a simple, easy-to-use, and widely adopted method.^7,11,20-30 Concerning the medication administration protocol, a preoperative dose administered 1 hour before the procedure is recommended, since this approach has been shown to be more effective than postoperative administration alone.^31-33 The medication dosage and dosing intervals have been suggested to follow the most commonly used clinical protocols for each drug. Therefore, larger multicenter randomized clinical trials employing standardized protocols for medication administration and pain assessment are warranted since they would enhance comparability across studies and strengthen the overall evidence regarding the efficacy of medications in orthodontic pain management.

Other systematic reviews have compared various pharmacological interventions for orthodontic pain control.^3,6,9,34-36 However, the present review specifically focused on the comparison between two widely used medications, which, despite their common use,⁷ have distinct mechanisms of action and different effects on tooth movement.¹² The substantial methodological heterogeneity among the included studies suggests that a more rigorous comparison of different methods or medications may be beneficial for improving the quality and consistency of future analyses.

Notably, this systematic review and meta-analysis was limited to evaluating the effectiveness of acetaminophen in comparison with ibuprofen in controlling orthodontic pain. Some of the included studies also assessed other medications and placebos; however, these results were not included in the analyses because they were beyond the scope of the present study.

Although 13 studies were included in the review, meta-analyses were conducted separately in terms of pain activity and assessment time point, yielding three to five studies per analysis. Funnel plots and tests for small-study effects are not recommended for analyses with fewer than 10 studies because of the limited power. To minimize publication bias, comprehensive searches included gray literature and clinical trial registries.

Although the results indicated no significant difference between acetaminophen and ibuprofen in terms of analgesic efficacy for orthodontic pain, the pharmacological profiles of these medications warrant consideration. Ibuprofen may interfere with tooth movement by inhibiting the chemical mediators essential for bone remodeling. In contrast, acetaminophen does not affect tooth movement, since it acts primarily on the central nervous system.¹² Therefore, the findings of this systematic review and meta-analysis suggest that acetaminophen should be considered a more appropriate option than ibuprofen for managing pain associated with orthodontic treatment. Notably, acetaminophen may cause hepatotoxicity,^10-12 so the patient’s medical history should be considered. In such cases, alternative approaches, including non-pharmacological methods, are recommended.

The wide variability in therapeutic protocols observed among the studies included in this systematic review highlights the lack of consensus regarding analgesic use for pain management in orthodontic patients. This scenario underscores the need for clear evidence-based clinical guidelines to guide therapeutic decisions. The absence of such guidelines may reflect underevaluation of pain control in orthodontic practice, suggesting that it still plays a secondary role among the clinical priorities of many professionals.

However, orthodontic pain represents a relevant aspect of treatment, since it can significantly affect patients’ quality of life and may lead to reduced adherence to treatment, increased missed appointments, and even premature treatment discontinuation.^3-5 Therefore, appropriate pain management should be regarded not only as an expression of empathy and commitment to patient well-being, but also as a determinant of treatment success and a hallmark of high-quality professional care.

Among the 13 studies included in this systematic review and meta-analysis,^7,11,20-30 five^20-22,24,30 did not include a placebo or control group; three^7,27,29 reported similar outcomes among the acetaminophen, ibuprofen, and placebo or control group; one²⁵ showed that only ibuprofen was superior to placebo; and four^11,23,26,28 reported that acetaminophen and ibuprofen were superior to placebo. These heterogeneous findings highlight the need for additional high-quality studies to assess the efficacy of these drugs. Nevertheless, a substantial proportion of available evidence^{11,23,26,28,31,33} suggests that both agents are effective and may be considered viable options for the clinical management of orthodontic pain.

Nevertheless, since ibuprofen can adversely influence the rate of tooth movement due to its local anti-inflammatory action,^10,12 and considering the lack of significant differences in pain control between the two drugs observed in this systematic review and meta-analysis, acetaminophen appears to be the preferred option, provided that the patient does not present with systemic conditions that contraindicate its use, such as hepatic impairment.

CONCLUSIONS

The results of this systematic review and meta-analysis indicate that acetaminophen and ibuprofen show no differences in pain control in patients undergoing orthodontic tooth movement. This conclusion is limited to comparisons between these two drugs and does not address their effectiveness relative to a placebo.

Considering the potential influence of ibuprofen on tooth movement and the lack of significant differences in the efficacies of acetaminophen and ibuprofen for orthodontic pain control, acetaminophen can be considered the preferred option for patients without systemic contraindications.