Previous systematic reviews have mostly analyzed single classes of oral medicaments, including steroidal (SAIDs) and non-steroidal anti-inflammatory drugs (NSAIDs), as well as opioid analgesics, not comparing one another and, thus, failing to provide conclusive results on the superiority of one over another approach. In addition, specific data regarding indications, timing and dosage of the post-operative endodontic oral medications prescription were often not clearly presented, thus not providing clinically relevant recommendations. Moreover, several reviews also evaluated antibiotics and pre-medications to control post-operative endodontic pain, which were both excluded from the present overview of systematic reviews of systematic reviews, because they contrasted with antibiotic stewardship standards proposed both by the American Dental Association [63] and the American Association of Endodontists [64] and with the attempt of avoiding polypharmacy [64], respectively, and they should, therefore, be considered not clinically advisable.

Systematic reviews reporting findings from subjects with cancer, osteonecrosis of the jaws or other systemic disorders possibly affecting pain perception or the efficacy of the investigated oral medications [65,66,67,68] were also not considered in the attempt to obtain generalizable data.

No data were retrieved differentiating vital from non-vital teeth, non-surgical initial endodontic treatment from retreatment and sessions number, neither in terms of post-operative endodontic pain incidence and severity nor management; thus, no specific recommendations could be formulated concerning pre-operative pulp conditions, the type of non-surgical endodontic treatment and single- vs. multiple-sessions procedures.

However, with regard to the type and dosage of post-operatively administered medications, steroidal anti-inflammatory drugs were shown to be effective in reducing pain intensity in the first 24 h after a primary root canal treatment. SAIDs’ analgesic efficacy was shown to be potentially influenced by the type and dose of the drug; no significant difference was nonetheless reported between dexamethasone (4 mg) and betamethasone (2 mg) [31].

Nonsteroidal anti-inflammatory drugs were the most common oral medicaments post-operatively administered to control pain, with ibuprofen being the most prescribed and investigated. Ibuprofen (600 mg) alone and ibuprofen (600 mg) combined with acetaminophen (1000 mg) were reported to be significantly more effective in post-operative endodontic pain control when administered 6 h after endodontic treatment and may be, therefore, recommended as a first-choice treatment in the first hours following non-surgical endodontic treatment. In addition, emerging data support the evidence that ketoprofen (50 mg) as well as naproxen (500 mg) might be even more effective than ibuprofen (600 mg) alone 6 h post-operatively [47]. However, only low to moderate evidence supports such a recommendation [48]. Moreover, multiple-dose regimens seemed to be more effective in pain control compared to single-dose, although no definite protocols were proposed [45].

Pain following endodontic treatment may be secondary to anatomical factors, such as apical foramen position, pulp tissue localization in areas where it cannot be removed without proper care and root canals that can be omitted without instrumentation, as well as to technical factors affecting or occurring during the procedure, such as an inaccurate determination of the working length. The last could, in turn, lead to excessive instrumentation, with extrusion of root canal debris beyond the apical foramen during instrumentation, an extension of the filling beyond the apex and an incorrect use of irrigants, specifically sodium hypochlorite and hydrogen peroxide, potentially causing iatrogenic periapical discomfort [50,51]. Mechanical and chemical damages to the periapical tissues would also determine an inflammatory reaction that causes pain. The severity of the pain has been reported to be dependent on several aspects, including the intensity of the injury, the intensity of the tissue damage and the inflammatory response’s intensity. The mechanical irritation that causes periapical inflammation includes over-instrumentation, irritants and drugs over the apical foramen and excessively extensive filling materials. Furthermore, the greater the amount of overextended material, the greater is the intensity of damage to the periapical tissues [62].

Pain after root canal treatment is a serious health problem that affects the quality of life in the short term and, sometimes, even in the long term. Root canal treatment is generally very effective in relieving tooth pain [50,52,53] when correctly performed. However, it has been reported that one in five patients, on average, receiving root canal treatment will experience a serious disturbance in their daily life due to post-operative endodontic pain [50] and that up to 10% of patients may refer to persistent pain until six months after endodontic treatment [51]. Indeed, endodontic therapy does not rely on biological consequences solely, but also on minimizing patient discomfort. The success of endodontic treatments is based on eliminating microbes from the root canal and on creating a local environment favoring healing, by performing appropriate shaping, 3D cleaning and, finally, a 3D obturation [5,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,54,55].

Silva et al. compared rotary instruments with hand files and concluded that a lower incidence of post-operative pain was recorded when rotary systems were employed [56]. Furthermore, these authors highlighted that rotary systems may reduce the overall risk of complications throughout the procedure, favoring both less debris formation and bacteria extrusion [56].

Based on the evidence, no significant differences in post-operative endodontic pain incidence, severity or control capability were reported for a single session when compared to multiple sessions endodontics [57,58]. However, numerous studies have also reported inter-appointment pain, putatively secondary to the imbalance in the host–bacteria relationship, induced by intra-canal procedures [5]. In such particular circumstances, pain may be due to the pathogenic effect of specific bacteria, such as Porphyromonas Endodontalis, Porphyromonas Gingivalis and Prevotella species, as proposed by various studies [59,60,61], or it may be linked to an individual’s host resistance [60]; it has been hypothesized that subjects who have a lesser ability to cope with infections may be more prone to develop clinical symptoms after endodontic procedures in infected root canals. Calcium hydroxide is considered an optimum root canal medication against microbes in multiple sessions treatments; such intra-canal medicaments have been found to be able to reduce the periapical infection, both decreasing the total count of those microbes present in the root canals and retarding the growth of new pathogens [49]. In addition to intracanal medications, several methods have been proposed to control pain occurring during endodontic treatment and resulting from inter-appointment exacerbations, comprising re-instrumentation, chirurgical incision, abscess drainage, occlusal reduction and systemically delivered medications [62].

Given that post-operative pain is very common and highly unpreventable [47], patients should always be advised that pain may be felt after the procedure, and considering the multi-factorial etio-pathogenesis of post-operative endodontic pain, practitioners should always steer clear of iatrogenic injury. Indeed, dentists should respect the working length during shaping, cleaning and obturation, both during root canal treatment and retreatment, accomplishing a correct access cavity to find all the root canals, using a crown down technique and respecting the apical third, avoiding debris, irrigants, gutta-percha and sealer extrusion over the apex and, finally, performing a correct obturation.