Comparison of Invisalign Aligners versus Fixed Appliance Treatment in pain perception: a systematic review and meta-analysis

Background: This systematic review aimed to compare the pain discomfort levels between Invisalign aligners comparing with traditional fixed appliances at multiple time points, through Pain Visual Analog Scale (VAS). Methods: Four electronic databases (Pubmed, Medline, CENTRAL and Scholar) were searched up to February 2019. There were no restrictions on year and publication status. Randomized clinical trials (RCTs) and case-control studies comparing pain perception through VAS in patients treated with Invisalign aligners and with labial appliances were included. Risk of bias within and across studies was assessed using Cochrane tool and Newcastle-Ottawa Scale (NOS) approach. Random-effects meta-analysis were conducted. VAS score at 1, 3 and 7 days, and analgesic consumption was collected. Pairwise and Binary Random-Effects Meta-analyses were used to synthesize available data. Results: At the initial search, a total of 87 articles were retrieved. Following the review protocol, 4 articles met the inclusion criteria and were included, with a total of 214 participants (139 females, 75 males). All studies were considered of high methodological quality. The results demonstrate that Invisalign aligners seems to be associated with significantly less pain than fixed appliances at 7 days after beginning the orthodontic treatment, although at 1 and 3 days the pain experience was similar in both orthodontics appliances. In regard to the type of material, SmartTrack aligners appear to give significantly better comfort for orthodontic patients than previous standard material, being that 3 days after appliance’s insertion this pain differential becomes significant, and this difference is more pronounced at 7 days. Conclusion: Patients treated with Invisalign experience less pain discomfort than those treated with fixed appliances and consume less analgesics. Overall, Invisalign promotes better pain and discomfort experience for the patient in the course of orthodontic treatment. Larger RCTs are needed to definitely demonstrate these findings throughout the orthodontic treatment.


Introduction
With the increase of esthetic requirements, facial's micro and macro-esthetic and smile have become a priority for adolescents and adults 1,2 . Consequently, patients lean to more esthetic and comfortable orthodontic treatments 3 .
According to Kesling, clear aligners were predominantly to minor tooth movement, usually at the end of orthodontic treatment or to treat minor alignment relapse 4 . In 1998, Invisalign aligners (Align Technology, California, USA) were introduced into the orthodontic market 5 . Since then, clear aligners have been popularized and quickly became the preferred orthodontic appliances for patients with great esthetic demands 6 . In 2013, Invisalign introduced SmartTrack, a new and highly elastic alignment material that allows a lower and more uniform force level. According to the brand, it offers patient better comfort, less pain and it is easier to handling. From that date, all patients were treated exclusively with this new material 7 .
In fact, clear aligners, like Invisalign, have much more esthetic attractiveness than conventional fixed appliances with brackets and wires 1 , and patients benefit by being able to have full access to remove clear aligners to eat and for oral hygiene. Still, patients treated with Invisalign have better periodontal health than those with conventional fixed appliances and there is better compliance with oral hygiene in teenagers 8- 10 .
Interestingly, pain experience research in orthodontic patients during treatment has been a research topic of interest . In fact, the pain experience progression after initial archwire placement in fixed orthodontic appliance is well established in the literature, comparing multistrand stainless steel and superelastic NiTi archwires [11][12][13][14][15][16][17][18] . However, overall pain perception during Invisalign aligners course of treatment and when compared with conventional fixed appliances are not well established.
Patients elect Invisalign aligners in hope that these appliances will have fewer negative impacts on their quality of life 19 . Therefore, it is essential to systematically evaluate whether there is a difference in pain perception between orthodontic fixed appliances and Invisalign aligners, and in this way, we can contribute to a more considered decision by the patient and the clinician about the following treatment.

Objectives
Given the increasing popularity of clear aligners, this systematic review aimed to compare the discomfort levels between traditional buccal fixed appliances with Invisalign aligners at multiple time points. The review PICO research question is "Does Invisalign have less pain discomfort impact than buccal fixed appliance treatment in orthodontic patients?", with the following statements: orthodontic patients (Patients -P); Invisalign treatment (Intervention/Exposure -I); Buccal fixed appliance treatment (Comparison -C); Pain discomfort (Outcome -O).

Protocol and registration
The present systematic review was conducted and reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines for reporting studies that evaluate health care interventions 20 (Appendix S1) and its extension for abstracts 21 . The protocol was previously defined and have been registered in the International Prospective Register of Systematic Reviews (PROSPERO; CRD42019124534). There were involved three researchers from the Orthodontics Department: DP, VM and ASD; and two researchers from the Clinical Research Unit: JB 3.
In vitro and animal studies;

5.
Editorials, opinions, narrative reviews, and technique description articles, without reported sample.

Search strategy
A total of four electronic databases (Pubmed, Medline, CENTRAL and Scholar) were searched systematically from inception to February 2019. The strategy used for the electronic search was the following: ("VAS"OR"Visual Analog Scale"OR"VAS scale"OR"pain perception"OR"pain")AND("Invisalign"OR"Invisalign aligner"OR"clear aligner")AND("orthodontic brackets"OR"bracket"OR"fixed appliance"). The reference lists of included articles and relevant reviews were manually searched. Gray literature was searched using the latter strategy in OpenGray.

Assessment of Validity
The eligibility of each study was assessed independently by two investigators (VM and DP), who screened the titles and/or abstracts of retrieved studies. Inclusion was dependent on the following eligibility criteria: randomized clinical trials and case-control studies who compare the discomfort level produced by traditional fixed appliances and Invisalign aligners at multiple time points. Final selection of studies was performed by three authors independently (VM, DP, JB), and verified by a fourth and fifth author (JJM, ASD), by reviewing the full text based on inclusion criteria above.
Discussion resolved any disagreements. Non-full papers, such as conference abstracts, thesis and letters to editors, were excluded.

Data extraction
Characteristics of the included studies and numerical data were extracted in duplicate by two authors (VM and DP) onto a predefined data extraction table: citation, publication status and year of publication, study design, setting, number of cases and characteristics of the participants (mean age, sex), VAS scores at multiple time points, type of fixed appliances, and analgesic consumption. Final data was reviewed by a third author (JB). Concerning additional data/clarifications, we tried to contact corresponding authors (on 10th of February 2019).

Quality assessment and Risk of Bias in Included Studies
The quality assessment of the eligible studies was performed by two independent reviewers (VM and JB). In areas of disagreements, a collective decision was obtained after a discussion between all authors to approach a consensus, with an opinion of a third reviewer (AD). Risk of bias of RCTs was assessed with the Cochrane Collaboration's tool. Case-control and cohort studies were appraised with the Newcastle-Ottawa Scale. ''Stars'' (points) were attributed for each methodologic quality criterion, and each study could achieve a maximum of 8 points. Studies with 7 to 8 points (80% or more of the domains satisfactorily fulfilled) were arbitrarily considered to be of high quality, studies with 5 to 6 stars were of medium quality, and studies with less than 5 stars were of low methodologic quality.
Disagreements between the review authors over the risk of bias in particular studies were resolved by discussion, with the involvement of a third review author (DP) where necessary.

Summary Measures & Synthesis of Results
For the conversion of median and interquartile range VAS score values to mean and standard deviations, Hozo et al. 22 procedure was used, under the assumption of normal distribution. Firstly, pain discomfort through VAS score of Invisalign versus traditional fixed treatment at 1, 3 and 7 days following their initial treatment appointment was appraised through DerSimonian-Laird (DS) randomeffect analysis. Secondly, Invisalign studies were subdivided according to the aligners materials, standard material and SmartTrack. Of the included studies, the percentage of analgesic consumption was also carried out at 1, 3 and 7 days after beginning orthodontic treatment through binary SD random-effects analysis. All random-effects meta-analysis and forest plots were performed using OpenMetaAnalyst (2016) software 23 . Quantity I² was used to measure to account for homogeneity and calculated through the χ2 test. Publication bias analysis was planned to be performed if, at least, we had 10 or more studies included 24 . All tests are two-tailed with alpha set at 0.05, except for the homogeneity test whose significance level cutoff will consider to be 0.10 due to the low power of the χ2 test with a limited amount of studies.

Study Selection
From the databases and other sources, the initial electronic database search resulted in a total of 87 record, resulting in 60 after duplicates removal. Following title and abstract screening, 9 studies were selected for full-text evaluation. Nevertheless, after full-text eligibility assessment, 5 studies were excluded (in detail in Supplemental Table S2). Therefore, the meta-analysis was performed on the basis of 4 articles. The flow chart of study selection together with reasons for exclusion is provided in Figure 1.

Study characteristics
Four prospective studies evaluated the pain discomfort of Invisalign orthodontic treatment through the comparison with buccal fixed orthodontics appliance. A total of 214 participants (139 females, 75 males) were included. The characteristic of the participants is shown in Table 1.

Risk of bias within studies
Only one RCT was included and was assessed as unclear overall risk of bias 6 . Table 2 shows the summary of risk of bias assessment for the RCT study according to the Cochrane Risk of bias tool. Table 3 (NOS Scale scores) shows the risk of bias assessment for the included studies. All three studies were considered of low risk of bias and, therefore, of high quality [25][26][27] .

Synthesis of results
Data from four studies including 165 patients reported pain discomfort through VAS score of Invisalign versus buccal fixed treatment 6,25,27 . All those studies provided data for pain discomfort at 1, 3 and 7 days following their initial treatment appointment, while two had data on a daily basis 6,25 .
Heterogeneity exists between the three studies at all time points (Fig. 2). So, we opted for a randomeffects model.
Similarly at 3 days after treatment, Invisalign patients experience in average 28.5% lower VAS score than patients with fixed appliances, but the difference is not statistically significant (MD = 1.56 , 95% CI: -0.16-3.29; Fig. 2). Meanwhile at 7 days follow-up, Invisalign patients experience in average 38.2% lower VAS score than patients with buccal fixed appliances, and the difference is statistically significant (MD =0.85 , 95% CI: 0.30-1.40; Fig.2).
In fact, although the difference in pain perception at 1 day after treatment beginning in patients treated with the Standard material of Invisalign (before 2013) versus SmartTrack (after 2013) is not significant (Fig. 3 Thus, Invisalign's SmartTrack material appears to be more comfortable for patients than previously manufactured clear aligner materials.

Additional analysis
A detailed number analgesic consumption after beginning orthodontic treatment at 1, 3 and 7 days are reported in three studies 6,25,27 . Overall, patients treated with Invisalign have significantly less analgesic consumption compared with fixed orthodontic treatment group control one day and seven days after treatment beginning (Supplemental Fig. S1). Overall, patients with fixed appliances consume more analgesics at the beginning of treatment.

Summary of Main Findings
This systematic review included one randomized and three case-control studies, with a total of 214 patients. The overall results demonstrate that Invisalign seems to be significantly associated with less discomfort rather than fixed appliances. Although at 1 and 3 days the results are not significant, at 7 days this difference is conclusive.
Notwithstanding, by accounting the type of material, SmartTrack appear to provide better comfort for orthodontic patients than the previous standard material. Notably, this differences becomes significant at 3 days after appliance insertion and turns more pronounced at 7 days. In fact, these results comply with a previous research where patients were transitioned to the aligners made with the SmartTrack material and experienced less pain intensity, pain duration, and less pressure upon insertion 7 . In addition, Invisalign patients reported less analgesics consumption compared to patients with fixed appliances, and present significant differences.

Quality of the Evidence, Limitations and Potential Biases in the Review Process
The strengths of this systematic review include the extensive unrestrictive literature search, with a rigorous and predetermined protocol implemented in each phase. However, there are limitations worth to mention among the included studies.
The included investigations were of small samples, and two of them lack sample size calculation 25,26 .
As well, there are a diversity of buccal brackets description since one did not refer the type of fixed appliances 25 , two used different self-ligated wire appliances 26 27 and another used a traditional buccal fixed appliances 6 . Though passive self-ligating systems result in minor periodontal ligament ischemia and therefore less discomfort 28 , literature evidences that pain experience in the beginning of treatment is independent of bracket type [29][30][31][32] . The type and size of archwires was only specified in two studies 6,26 , which is also a limitation. However, previous studies have found no significant differences in the pain perception using different archwires types 29,33,34 .
Moreover, only one study 6 performed allocation concealment, while the remaining three [25][26][27] did not randomly assigned the treatment modalities due to their cohort design nature. In fact, well-conducted and adequately informed "gold standard" RCTs are the epitome in clinical research 35,36 . The main advantage lies in the random allocation of patients minimizing patients selection bias 37 . However, randomizing adult patients is not simple, since some of whom are unwilling or unable to comply with the random assignment due to esthetic reasons 26 . This difficulty limits the ability to completely randomize the study. The fact that the patient has a choice demonstrates personality traits, which can impair the perception of pain.
Additionally, pain experience is a notoriously subjective response and there is a non-linear relationship upon multiple factors such as age, gender, individual pain threshold, the magnitude of the force applied, present emotional state and stress, cultural differences, and previous pain experiences 12,15,[38][39][40][41][42] . A hypothetical limitation would be the fact that there is an unbalanced gender ratio. However, gender has no significant effect on orthodontic pain perception 12,15,41,43 , except in adolescents, where females have less pain tolerance than males 44,45 .
Finally, the placement of SmartForce attachments since the beginning of the treatment with Invisalign is relevant in pain perception, because they make more pressure during the insertion of the aligner.

Conclusions
Within the limitations of this systematic review, the results show that patients treated with Invisalign experience less pain and discomfort than patients treated with traditional buccal fixed appliances.
This becomes more significant since the SmartTrack introduction into the Invisalign aligners. This information may clarify patients about what to expect during the beginning of orthodontic treatment.
In the future, larger randomized clinical trials are needed to definitely demonstrate Invisalign's better comfort over traditional fixed appliances throughout the orthodontic treatment.

Implications for Clinical Practice and Research
These findings may help both patients and clinicians in the treatment modality decision, concerning pain parameters and analgesic consultation, in the first phase of orthodontic treatment.
In the main, randomized clinical trials are needed to perform a robust comparison of Invisalign aligners and buccal orthodontic fixed appliances. Aspects concerning long-term outcomes appraisal, objective measurements of patient-centered reported outcomes (such as quality of life), and adverse effects (including allergies, periodontal damages and functional impairment) are important factors to consider.

Conflict of interest statement
Nothing to declare.

Ethical committee information
Nothing to declare.