## 1 Introduction  
The revised International Association for the Study of Pain (IASP) (2020) defines pain as an unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage [1]. Moreover, pain is a subjective response to a stimulus with significant variations, relying upon factors such as gender, age, the magnitude of the stimulus, the unique pain threshold, the patient's emotional state, cultural dissimilarities, and prior pain experiences [2, 3]. Patients who undergo orthodontic treatment (OT) may experience pain associated with various fixed orthodontic appliances [4, 5] and often describe the pain as tension, pressure, ache, or soreness of the teeth [4, 6]. Orthodontic pain intensity begins from 2 h to a peak at bedtime or 24 h after the force is applied, and the pain gradually decreases after the seventh day [4, 7, 8]. Orthodontic pain results from inflammation, pressure, ischemia, and edema in the periodontal ligament (PDL) and tissues following the application of orthodontic forces [9, 10]. The inflammatory reaction is mediated by inflammatory mediators that work on target cells to eradicate the damaging agent and repair the tissue [11]. Various inflammatory mediators in the PDL, such as prostaglandandins, histamine, bradykinin, serotonin, and substance P mediators, can be found in the bloodstream during inflammatory reactions or are created at the inflammation site [11; 12]. Inflammatory mediators balance the inflammatory response by changing the local microenvironment [11; 13]. These mediators stimulate vasodilation and increase vascular permeability in the inflammatory cycle, which are essential mechanisms connected with edema and hyperemia formation, which will induce pain and discomfort [11; 13; 14]. Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) such as Ibuprofen are conventional analgesic drugs (CADs) used to reduce orthodontic pain [3; 15]. Ibuprofen is a monocarboxylic acid that is propionic acid in which one of the hydrogens at position 2 is substituted by a 4-(2-methyl propyl) phenyl group, and the molecular formula is C\({}_{13}\)H\({}_{18}\)O\({}_{2}\) (Figure 1) [16; 17]. The NSAIDs work by blocking the enzyme cyclooxygenase (COX) activity, which modulates the modification of prostaglandandins from arachidonic acid in the cellular plasma membrane [15; 18]. In this regard, NSAIDs decrease pain by COX inhibition, which represses prostaglandinin production. However, prostaglandandins, including PGE1 and PGE2, are crucial intermediates of bone resorption. Therefore, the interference in bone remodeling and orthodontic tooth movement (OTM) may occur by suppressing prostaglandin activity with NSAIDs [15; 19]; nonetheless, the clinical impact of NSAIDs on the rate of OTM remains inconclusive. Further, Ibuprofen has systemic side effects, like allergic responses, thrombocytopenia, gastrointestinal discomfort, high blood pressure, and multiple unfavorable reactions [20; 21; 22]. Acetaminophen (Paracetamol) is another CAD used to relieve pain; it is suggested as a first-line pharmacological treatment by international guidelines as an analgesic and antipyretic for children [23]. Furthermore, Acetaminophen (Paracetamol) inhibits prostaglandinin synthesis in the central nervous system, not in peripheral tissues [24; 25], so Acetaminophen (Paracetamol) is not an anti-inflammatory agent and does not control prostaglandinin synthesis and movement of the tooth, unlike NSAIDs [25; 26]. Also, Acetaminophen (Paracetamol) is known as safe in suitable and controlled dosages [27; 28]. However, possible side effects of Acetaminophen (Paracetamol) in children may include renal or hepatic collapse with overdoses or extended usage [23; 29]. Thus, different studies have offered alternative non-pharmacological methods for managing orthodontic pain [30], such as chewing gum [31], low-level laser therapy [32], vibratory stimulation of the periodontium [33], transcutaneous electrical nerve stimulation [34], and bite wafers [2].