Introduction. There is a growing demand for more aesthetic, comfortable, and faster orthodontic treatments, and clear aligners emerged as a solution to fulfill this need. However, the effectiveness of clear aligners to treat complex malocclusions is yet contentious. The use of acceleration methods could improve the efficacy of clear aligners by stimulating cells' mechanobiology through numerous pathways, but this hypothesis is still poorly explored. Objective. We aimed to monitor the release profile of an inflammatory marker-the interleukin-1β-and to evaluate its relationship with self-reported pain scores with and without the use of acceleration techniques during an orthodontic treatment requiring difficult tooth movements with clear aligners. Case Report. Here, we report a case of a 46-year-old female patient who presented functional and aesthetic complaints. Intraoral examination revealed a diminished overjet and overbite, rotation of teeth 45 and 24, absence of teeth 25, 35, and 36, buccolingual dislocation of tooth 21, a tendency to a Class III malocclusion, and a 2 mm left deviation of the lower midline. This study is divided into three stimulation phases: no stimulation, mechanical vibration stimulation, and photobiomodulation. Interleukin-1β levels in gingival crevicular fluid samples from the pressure side of six selected teeth were evaluated at four time points after the orthodontic treatment onset. Pain monitoring in those teeth was performed using a visual analogue scale at the same time points. Results. Interleukin-1β protein production peaked 24 h after treatment onset. Complex movements were associated with increased self-reported pain. Conclusion. Clear aligners show limitations in solving complex tooth movements, even when combined with acceleration. The development of customized and programmable stimulation microdevices integrated into “smart aligners,” which could be designed to specifically stimulate the direction of movement and stimulation parameters and could constitute a solution to optimize the orthodontic tooth movement with clear aligners.