The underlying mechanism of pain during orthodontic tooth movement is a result of the complex interplay between vast numbers of neurons and chemical mediators in both the central and peripheral nervous systems. It is well known that orthodontic pain is primarily due to an inflammatory reaction in the periodontium, which accompanies orthodontic tooth movement.¹² The application of orthodontic force results in a localized region induces ischemia, inflammation, and edema in the periodontal ligament space²⁶ and activates a cascade of proinflammatory mediators. One of these mediators is the enzyme cyclooxygenase-2 (COX-2), a critical component in the synthesis of prostaglandin,²⁷ which is targeted by nonsteroidal antiinflammatory drugs (NSAIDs). Nociceptive stimuli exerted by orthodontic appliances are primarily detected by sensory fibers²⁸ such as C fibers (unmyelinated) and thinly myelinated Aδ fibers in the pulp and periodontal ligament.²⁹ Other substances that either activate or sensitize nociceptors during inflammation include tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), IL-1β, bradykinin, enkephalin, serotonin, dopamine, glutamate γ-amino butyric acid, and histamine.^30–34 Studies have demonstrated that elevated levels of these compounds are associated with hyperalgesia.^35,36 In addition, the activated proinflammatory mediators can stimulate the release of neuropeptides from the afferent nerve endings into the surrounding tissues.³⁷ Substance P and calcitonin gene-related peptide (CGRP) are two potent neuropeptides that cause neurogenic inflammation.^37–42 These sensory neuropeptides enhance inflammation through interactions with epithelial cells to induce vasodilation and increase blood vessel permeability.^43,44 They also lead to mast cell degranulation and further release of proinflammation mediators such as histamine and serotonin.⁴⁵ These inflammatory mediators trigger the release of more neuropeptides, contributing to a continuation and intensification of the inflammatory process.²⁸ Substance P also increases the levels of various cytokines, such as TNF- α, IL-1β, and IL-6.^33,42 CGRP stimulates the release of IL-6, IL-8, and TNF-α.⁴² These cytokines serve as signaling messengers between immune cells and are important in bone resorption, deposition, and remodeling.⁴⁶ IL-1β is released by fibroblasts of the gingiva surrounding the teeth during orthodontic tooth movement and is involved in bone remodeling.^47,48 IL-6 is a regulator of the immune response during inflammation and the formation and activity of osteoclasts.^49–51 TNF-α is synthesized and released by monocytes and macrophages and may be related to bone remodeling.⁵²

The afferent fibers have their cell bodies residing in the trigeminal ganglion of Meckel cave and transmit electrical signals to the central nervous system. They ascend the trigeminal spinal tract and enter the trigeminal sensory nuclear complex. From the trigeminal brainstem complex, the nociceptive signal is transmitted to the thalamus and eventually to the cerebral primary somatosensory cortex, where the location of the signal is discriminated. Top-down neural pathways modulate the nociceptive stimuli coming from the periphery.⁵³ Although several brain areas are involved in pain processing, still little is known about how pain is encoded in the brain. However, it is clear that the pain and salience brain networks overlap.⁵⁴

The initial pattern of pain experienced by patients undergoing traditional multibracket orthodontic appliance therapy has been long studied and well documented.^2,9,55–58 Pain appears approximately 2 to 3 hours after orthodontic forces are applied to the teeth, with peak levels frequently occurring within the first 24 hours after archwire placement, followed by a steady decrease toward baseline levels within 7 days (Fig. 18.1).^2,59–63 These findings have been confirmed in several racial and ethnic groups^56,64–67 and through the use of ecologic momentary assessment.⁶⁸ There also appears to be a diurnal variation in pain experienced by patients, with higher levels occurring in the evenings and nights.⁶⁹

Overall, patients are generally able to tolerate and adapt to new appliances within 1 week after placement.⁷⁰ However, female patients in middle adolescence have been reported to experience more pain than age-matched males and younger patients when exposed to orthodontic procedures.⁷¹ In addition, orthodontic pain is significantly affected by menstrual phase, with the pain levels being higher in the luteal phase.⁷² While there is conflicting reports on the effect of age on orthodontic pain perception,³ there is substantial evidence that the type of malocclusion and the amount of crowding have little effect on pain experienced during orthodontic treatment.^73,74 These findings suggest that pain is likely most affected by other factors, including hormonal and psychological variables.¹² One such example is anxiety,⁷⁵ which among other things can be dependent on the relationship with the orthodontic care provider.⁷⁶

Orthodontic pain associated with CAT has been investigated in a limited number of studies. CAT appears to follow a similar pattern of pain progression in terms of peaking at 24 hours and trending toward baseline levels after 7 days.^{21,60–62,77} However, to date, CAT has mainly been associated with more intermittent forces as compared to conventional treatment with multibracket appliances, although several companies are focusing on developing materials that may provide more gentle and continuous forces. Only a limited number of studies exist that examine orthodontic pain in patients undergoing CAT with Invisalign’s latest generation multilayered polyurethane-based polymer, SmartTrack. These studies show a maximum patient-reported pain score of 20 mm on a 100-mm visual analogue scale (VAS), which may be considered mild and of limited clinical significance.^62,77 In previous literature, Exceed-30 thermoplastic material was used in the older generation, and coincidently these studies showed significantly higher reported pain scores in the first week of treatment (up to 40 mm on VAS).^21,60,61 Limited evidence suggests SmartTrack may be more comfortable than older generation materials,⁷⁸ but further studies are needed to validate this.

Interestingly, with continued active tooth movements of the subsequent aligner stages, there is less pain reported by patients compared to the first stage aligners even if the first stage aligners are programmed to be passive (without active tooth movements).⁷⁷ This perhaps could be a result of the accuracy, fit, and deformation of the first trays,⁶¹ the introduction of iatrogenic posterior occlusal interferences,^79,80 or the apprehension and stress involved with starting orthodontic treatment with a new appliance.^16,75 Indeed, pain perception with CAT, especially during the first stage, is significantly related to an individual’s psychological stress and anxiety.⁷⁷

In general, when compared to traditional multibracket appliances, CAT results in less reported pain and improved patient experience. Miller et al.⁶⁰ conducted the first study evaluating the differences in pain and impact on quality of life experienced by patients undergoing CAT versus multibracket appliance therapy. This was a prospective longitudinal cohort study with 33 CAT patients and 27 multibracket appliance patients. The participants were asked to use a daily diary for 7 days, measuring functional, psychosocial, and pain-related impacts.⁸¹ The diary consisted of questions adapted from the Geriatric Oral Health Assessment Index,⁸² a 5-point Likert scale for demographic data, and a visual analog scale for pain. The results showed that the progression of pain in aligner treatment followed a similar pattern to multibracket appliances, in which pain peaked after 24 hours and gradually returned to normal. Additionally, although the initial levels of pain were higher for the multibracket appliance group, along with higher levels of analgesic consumption, both groups recovered to baseline within 7 days.

In a subsequent study by Shalish et al.,²¹ 68 patients being treated by either buccal multibracket appliances, lingual multibracket appliances, or CAT were recruited to complete a health-related quality of life questionnaire^{22,23,83–85} and a 5-point scale for dysfunction during the first week and on day 14. Their results showed the average initial pain levels were consistently higher in the lingual multibracket appliance and clear aligner groups, with analgesic consumption paralleling the dynamics of the pain levels (although the difference did not reach statistical significance). In all groups, the pain levels subsided within 1 week. These results contradict the findings by Miller et al.,⁶⁰ which the authors attributed to a greater mechanical force being applied in the aligner group compared to the buccal multibracket appliance group.

To further elucidate and compare pain levels between these orthodontic treatment modalities, Fujiyama et al.⁶¹ conducted a prospective clinical trial with 145 patients receiving either CAT, multibracket appliance therapy, or a hybrid treatment combining both modalities. Using VAS, the participants were asked to record their pain levels at time points of 60 seconds, 6 hours, 12 hours, and 1 to 7 days post appliance insertion. This was repeated at weeks 3 and 5 after appliance delivery. Their results illustrated a similar pattern of pain progression during the first week of appliance delivery for all groups studied. However, the overall pain levels were significantly more intense and longer lasting for the multibracket appliance group than either the aligner or the hybrid group.⁶¹

In a recent study by White et al.,⁶² patients were randomly allocated to either clear aligner or multibracket appliance treatment groups to investigate differences in their pain levels. The participants were asked to complete a daily diary with pain measured on VAS. The diary was completed at initial appliance delivery, daily for the first week, as well as the first 4 days after their next two follow-up appointments. The pattern of pain progression during the first week following initial appliance activation was in general agreement with previous studies.^{2,21,55,56,60,86} The clear aligner group experienced consistently lower discomfort than the multibracket appliance group during most of the first week, with statistically significant differences observed after 2 to 3 days. Moreover, analgesic consumption was more frequent in the multibracket appliance group, and their rate of consumption closely mirrored the pattern of pain progression during the first week. Similarly, over a relatively longer term of 2 months, the level of pain was less in the aligner group than the multibracket appliance group. The patients in the multibracket appliance group may have experienced an increased initial inflammatory response, which led to increased sensitization of the nociceptors and higher pain sensation in subsequent follow-up appointments.⁶²

The results of White et al.,⁶² Fujiyama et al.,⁶¹ and Miller et al.⁶⁰ comparing pain and discomfort between CAT and multibracket appliances are in general agreement with one another, as well as with past studies that demonstrated multibracket appliances may cause more pain than removable appliances.^12,70,87,88 As mentioned earlier, these results were in contrast to the findings from Shalish et al.,²¹ who reported the pain was greater in patients treated with aligners than multibracket appliances. One possible explanation for this discrepancy could be the variations in the initial archwires used between the studies. For example, the classic nickel titanium (NiTi) or nitinol wires used in the Shalish et al. study have been shown to display higher peak discomfort than the superelastic copper NiTi wires used in White et al.^89,90 Furthermore, the White et al. study was the only one to utilize SmartTrack, a new aligner material brought to market by Align Technology in 2013,^91,92 whereas the previous studies used the older Exceed-30 aligner material. Limited evidence suggests SmartTrack may be more comfortable than previous materials,⁹³ although further studies are needed to verify this.⁶² Lastly, Shalish et al. speculated that the differences in pain levels observed may possibly have been due to a higher level of mechanical force being applied early in treatment for the aligner group.

In summary, although orthodontic pain exists with CAT, the current evidence seems to suggest it is of a lesser degree than multibracket appliances, especially during the first week. However, additional studies providing more substantial data are needed. As would be expected, activation in the aligner tray has been reported as the most frequent cause of pain and discomfort.⁶¹ However, other issues leading to pain in association with clear aligners might include nonsmooth edges, tray, and attachment deformation.⁶¹

Clinical and pain assessment literature continues to be focussed on identifying and managing specific cognitive and psychological factors that are related to the individual’s experience of pain. In orthodontics, pain is a common sequela and expected with treatment. However, it is apparent clinically that the perception of pain varies considerably across individuals when the same stimulus, such as an initial light archwire, is activated. The expected pain from an orthodontic adjustment is generally believed to be relatively minor and self-limiting; however, some patients will report a much different experience.⁷⁵ It is generally accepted that particular affective and cognitive behavioral factors contribute to these differences in individual pain perception.⁹⁴ Specifically relevant to medical and dental settings, pain perception is influenced by factors such as somatosensory amplification, anxiety, depression, and catastrophizing.^95–104

It has been shown that patients with prolonged pain during orthodontic treatment exhibit higher levels of anxiety than individuals with pain of short duration.¹⁰⁵ Furthermore, experimentally induced orthodontic pain via elastomeric separators is greater in individuals who exhibit higher levels of trait anxiety and somatosensory amplification—a tendency to perceive normal somatic and visceral sensations as being relatively intense, noxious, and disturbing¹⁰⁶—as compared to individuals with low levels of both.⁷⁵ Of importance, anxiety and other mood disorders have been found to be related to increased frequencies of waking-state oral parafunctional behaviors, such as waketime tooth clenching,^107–109 which are also associated with temporomandibular disorders.^79,110,111 Therefore, it might be questioned whether anxiety, orthodontic pain, and jaw motor behavior are intertwined.

Recently, we performed a large web survey¹¹² and recruited 45 individuals subdivided into groups with high, intermediate, and low levels of trait anxiety.^113,114 Elastomeric separators were applied to the molars and pain and frequency of tooth clenching episodes were recorded for 5 days. A significant correlation orthodontic pain and frequency of tooth clenching was observed. In participants with high anxiety, the decrease in orthodontic pain was paralleled by a decrease in the frequency of waketime tooth clenching episodes. These results suggest that individuals with high trait anxiety may respond with an avoidance behavior (decrease of jaw motor activity) to orthodontic stimuli as a method to reducing their pain experience. The relationship between jaw motor activity and orthodontic pain is supported by a recent study that demonstrated a reduced masticatory performance in orthodontic patients during the period in which they reported the maximum levels of pain and crevicular IL-1β.¹¹⁵ However, there is some evidence of increased jaw muscle activity with CAT,^116,117 leading to jaw muscle tenderness of limited clinical significance.⁷⁷

Beck et al. estimated the contribution of psychological factors to orthodontic pain.⁹⁶ Of interest, for every pain catastrophizing scale (PCS) magnification score of 1 unit higher, the relative risk of being a high-pain responder was 1.6.⁹⁶ Magnification refers to an individual’s tendency to exaggerate the threat value of nociceptive inputs.⁹⁵ In this study, the authors showed that cold sensitivity significantly predicts the pain experienced, with those reporting greater scores for cold sensitivity having greater orthodontic pain. This result supports the hypothesis that somatosensory amplification plays a major role in orthodontic pain experience.⁷⁵ Evaluation of the abovementioned psychological constructs in a clinical setting utilizing validated questionnaires is advisable to identify individuals who may be more sensitive to pain and discomfort during orthodontic therapy. Anxiety and symptom perception management might be recommended for those susceptible individuals.

In the last decade, several reviews and clinical studies have been published on the management of orthodontic pain. It is well known that pharmacologic approaches with over-the-counter analgesics are effective in managing orthodontic pain. In particular, acetaminophen (paracetamol) is usually prescribed in place of NSAIDs to avoid possible effects on the rate of tooth movement.^118,119 Indeed, NSAIDs have been reported to interfere with the synthesis of prostaglandin E2 (PGE2), which is known to be an important chemical mediator during the bone remodeling process.^120,121 A recent Cochrane review,¹²² including 32 randomized controlled trials (RCTs) and 3,110 participants aged 9 to 34 years, did not find any evidence of a difference in efficacy between NSAIDs and paracetamol at 2, 6, or 24 hours postintervention. They concluded that analgesics are more effective at reducing orthodontic pain than placebo or no treatment.

Sandhu and Leckie¹²³ examined the diurnal variation of pain in 85 orthodontic patients. Consistent with the abovementioned studies, pain was reported to peak after 24 hours. Interestingly, during the peak period, orthodontic pain was lower during the afternoon as compared to the night and morning. Therefore, the authors suggested that patients should be advised to take analgesics accordingly and need not be prescribed routine analgesics to be taken every 6 to 8 hours. In addition, they suggested that preemptive administration of analgesics may be more effective than posttreatment administration, as the traditional administration at regular intervals does not consider temporal variations in orthodontic pain. However, the previously mentioned review¹²² indicated there is very low evidence suggesting preemptive ibuprofen gives better pain relief at 2 hours than ibuprofen taken posttreatment. Finally, it must be noted that the combination of acetaminophen plus ibuprofen provides greater analgesic efficacy than acetaminophen or ibuprofen alone.¹²⁴

Special considerations should be made for patients with a history of regularly taking pain medications. Indeed, a recent literature review (which included animal studies) suggested that long-term consumption of pain relievers can significantly affect the rate of orthodontic tooth movement.¹²⁵ Surprisingly, they found that animals in treatment with ibuprofen did not show a significant decrease in orthodontic tooth movement, as some previous human studies had shown. On the other hand, long-term administration of indomethacin, ketorolac, and high doses of etoricoxib decreased the amount of tooth movement. However, caution should be taken when interpreting these results due to the questionable quality of evidence that is available.

Several nonpharmacologic approaches have been considered to manage orthodontic pain. In another recent Cochrane review,¹²⁶ Fleming et al. included 14 RCTs with 931 participants and analyzed the effects of low-level laser therapy (LLLT), vibratory adjuncts, experimental chewing adjuncts (e.g., bite wafers and chewing gum), and psychosocial and physical interventions on orthodontic pain. They concluded that laser irradiation may help reduce orthodontic pain in the short term. On the other hand, evidence to support other methods is of low quality.

It is the opinion of the authors that nonpharmacologic interventions should be used whenever possible to reduce orthodontic pain (Table 18.1), provided they do not expose patients to harm or additional costs during treatment; they should be used especially when a medical condition prevents the use of recommended analgesics. Of foremost importance, clinicians should establish a relationship of trust with patients and improve their communication skills to reduce nocebo and favor placebo effects. Overall, a proper pain management approach would require a careful baseline assessment of pain predictors, psychological factors, and patient expectations. Moreover, placebo and nocebo effects should be considered when communicating with patients. Blasini et al. highlighted that negative patient-practitioner interaction should be avoided and that communication with patients should be well-balanced by not providing excessive negative information with regard to side effects and limiting information regarding benefits.¹²⁷

Table 18.1

Strategies to Reduce Pain During Orthodontic Treatment

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