Pain is an undesirable experience after orthodontic appliance activation. The pain is local and ideally should be managed topically [23]. No standard method has yet proposed for reducing pain in orthodontic patients. In the present study, a novel method for drug delivery was evaluated for pain relief in orthodontics.
The result of the present study regarding benzocaine was in agreement with a previous study on benzocaine chewing gum, where the authors observed that benzocaine chewing gum was significantly more effective than placebo and ketoprofen chewing gum at 2 hours [20]. However, in both studies, the effect did not last. The first administration of both drug forms was immediately after orthodontic appointment. Considering the short half-time of benzocaine [28], it seems that the drug was useful in first hours. Although the effect was not permanent, this effect can break the pain cycle and help the patient to tolerate the pain more easily. As Cooper et al. stated, after pain onset, some factors can increase or decrease pain by amplifying and breaking the pain cycle [29]. Benzocaine can be a breaking factor.
Maximum pain in benzocaine group was at 10 am in day 2. This is comparable to the results of previous studies [30–32]. In a systematic review about the level of cytokines after orthodontic force, maximum level of IL-1β released 24 hours after force application and this increase was correlated with increased pain perception [33]. It has been shown that PGE2 is the leading cause of pain in first hours. However, IL-1β is the cause of pain 1 day after force application [34]. In a meta-analysis about the effect of Ibuprofen in relieving orthodontic pain, the same effect was seen. In other words, Ibuprofen was effective in pain reduction in the first day, while ineffective at 24 hours.[35] This can be attributed to the mechanism of pain control by these two drugs, Ibuprofen and benzocaine. Benzocaine stabilizes the membrane of neurons reversibly and decreases sodium channel permeability, hence inhibiting neuron depolarization [36]. There are evidences that benzocaine can inhibit mechano-sensitive sodium channels in heart and gastero-intestinal tract.[37] There is not any evidence that sodium channels in PDL are similar to aforementioned channels. However, considering the mechanical sensitivity of PDL, this may come true. So that, benzocaine reliefs pain by changing sensory guidance and have little to do with the basic mechanism of pain, that is cytokine release, especially in hours in which cytokine levels are maximum. The same may be true about the effect of Ibuprofen, which act by inhibiting arachidonic acid and prostaglandin formation, meaning that it has no effect on interleukins [23].
According to Fig. 1, after the first day, the pattern of change in pain is similar between the groups. This can be attributed to tachyphylaxis phenomenon, meaning that after repeated administration of anesthetic drug, the drug effect is reduced.[38] The cause of this phenomenon is unknown but some factors like edema, tissue hemorrhage, coagulation, changes in distribution of local anesthetic drug, hypernatremia and decrease in PH can play a role [39].
According to Tables 3 to 5, pain perceived in placebo and control groups show more fluctuation in amount in comparison with benzocaine group, which show more steady pain levels. Pain experienced at 10 am in second day was the maximum pain level in benzocaine group, and the level of pain in that time point was similar to those of the other two groups. However, this pain was not the maximum pain level in placebo and control groups.
Minimum level of pain was perceived at day 7 in all study groups. This finding was similar to those of other studies [16, 20, 40, 41]. Some authors have stated that at day 7, 42% of patients were still experiencing pain [32, 42]. The same was seen in our study where 49.4% of patients experienced pain at day 7.
An interesting finding of the present study was that, mean level of pain was somehow low. Maximum pain level did not reach to 45 according to VAS, even in placebo and control groups. This may be due to placebo effect [43], it seems that, behavioral factors, including reassurance and attention distraction are effective in managing orthodontic pain [44]. Giving a VAS questionnaire and explaining about pain, may reassure patient that his/her pain matters, even in control group. Interestingly, Pain level was not different between placebo and control groups. Cross-over design may have an assimilating effect on placebo effect of groups.
It is believed that in all patients, pain perceived at first appliance activation is more than the other appointments [15]. In other words, pain level is decreased after first appointment. Considering the fact that interventions was done in 3 sequentially appointments in cross over design, the questions are raised whether the results of interventions are comparable. However, in order to decrease this effect, we defined the sequence of interventions randomly.
In this study 5% benzocaine was added to toothpaste. This concentration was chosen to decrease the risk of overdoses and drug poisoning. In our previous studies we used 20% benzocaine in chewing gum [20]. However, the drug distribution with toothpaste carrier is different from those carried in chewing gum. So that, it was not safe and ethical to increase the concentration to 20%. More studies are needed to assess the safety of increasing the drug concentration.
Age and gender can affect pain expression [4]. However, results of studies regarding this issue show controversy [42, 45]. Cross-over design eliminated the probable effect of these factors on pain perception. In the present study, the number of female subjects was more than male subjects (24 versus 10 in sampling). 5 male subjects versus 1 female subject were excluded further. This unequal distribution made it impossible to distinguish pain perception in females and males. This difference in distribution can be attributed to many factors including:
1. The number of females who experience pain in first appointment are more than males. The same was seen in Scheurer et al. and Kvam et al. studies [32, 46]. However, the findings were so controversial and some studies did not find any difference between genders regarding pain perception.[47]
2. The number of female orthodontic patients in orthodontic department was more than males.
3. More females were volunteer to attend in our study and they cooperated better during the study.
In present study, Visual Analogue Scale (VAS) was used as a measurement tool for pain assessment. VAS is an easily accessible, valid and reliable tool and because of its numerical and illustrative format, intercultural differences can not affect its validity [48]. However, its limited ability in differentiating sensory and afferent pain, may cause some errors [49]. So that, some authors have proposed measuring the level of chemical agents as a tool for pain perception [50]. Nevertheless, some authors believe that the level of these agents is not necessarily correlated with perceived pain [51]. More studies are needed to validate these methods.
Toothpaste is a novel carrier for drug delivery and is claimed to be able to reach the drug to local blood flow [52]. In addition, no adverse event was observed in the study subjects and toothpaste was a safe carrier for analgesic drugs. Patients’ tolerance to benzocaine toothpaste was well.
Finally, it should be emphasized that pain has multifactorial and subjective nature and many factors can affect study findings, including age, gender, time of drug delivery, emotional status, cultural differences and previous experiences of patients [15]. In this study, we tried to decrease individual differences by a cross over design, randomization of groups and double blinded design.