## 4 Discussion
### 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 one of them lack sample size calculation [31]. As well, there are a diversity of fixed appliances description since one did not refer the type of buccal fixed appliances [31], one used self-ligated fixed appliance [33], three used a twin-bracket fixed appliance [6], and one also had lingual brackets [32; 34]. Though passive self-ligating systems result in minor periodontal ligament ischemia and therefore less discomfort [35], literature evidences that pain experience in the beginning of treatment is independent of bracket type [36; 37; 38]. The type and size of archwires were described in four studies [6], though they differed in type and size among them, which is also a limitation worth mentioning. Nevertheless, previous studies have found no significant differences in the pain perception using different archives types [36; 39; 40]. Furthermore, [PERSON] et al. [33] have placed the fixed appliance exclusively in the maxillary arch during the first week of treatment, and this may explain also the observed heterogeneity. Moreover, only one study [6] performed random selection, while the remaining four [31; 32; 33; 34] did not randomly assigned the treatment modalities due to their cohort design nature. 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 [32]. 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. Notwithstanding, the RCT included in this review [33] lacked allocation concealment contributing to the overall concern on the risk of bias [33]. Allocation concealment is predictably difficult to achieve in this type of studies in which the intervention is a removable appliance and its control a fixed appliance. Additionally, pain experience is a notoriously subjective response and there is a nonlinear 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 [14; 17; 19; 41; 42; 43; 44]. A hypothetical limitation would be the fact that there is an unbalanced \begin{table}
\begin{tabular}{c c c c c c c c} \hline \hline
**Subgroup Meta-Analysis** & **n** & **OR** & **95\% CI** & _p-Value_ & **I\({}^{2}\) (\%)** & **Tau** & _p-Value_ \\ \hline
**Day 1** & **3** & **0.15** & **(0.04; 0.50)** & **<0.001** & **84.9** & **49.3** & **0.14** \\ \hline
**Day 3** & **3** & **0.75** & **(0.11; 5.10)** & **<0.001** & **83.0** & **81.0** & **<0.001** \\ \hline
**Day 7** & **3** & **0.23** & **(0.52; 0.99)** & **<0.001** & **64.2** & **0.0** & **0.79** \\ \hline
**Overall** & **3** & **0.30** & **(0.12; 0.72)** & **<0.001** & **80.5** & **58.8** & **0.01** \\ \hline \hline \end{tabular}  
* Test for subgroup differences (random effects model): Q = 1.97, \(p\) = 0.3734. OR–Odds Ratio.  
\end{table} 
Table 4: Subgroup meta-analysis of Analgesic consumption at 1, 3 and 7 days of follow-up. gender ratio. However, gender has no significant effect on orthodontic pain perception [14; 17; 19; 45], except in adolescents, where females have less pain tolerance than males [46; 47]. Finally, placing attachments at the beginning of the clear aligner treatment is relevant for pain perception because they cause more pressure during the insertion of the aligner. Among the included studies, [PERSON] et al. [31] did not place attachments, two studies used attachments since they placed the first aligners [6] and [PERSON] [33] delayed the attachments placement until the third set of aligners.