Introducing a passively targeted formulation of diclofenac potassium for application in endodontics to minimize renal and gastrointestinal side effects

One of the most significant obstacles to root canal therapy is the management of pain caused by irreversible pulpal inflammation. The American Association of Endodontists states that symptomatic irreversible pulpitis (SIP) is a clinical case that necessitates urgent intervention because the vital, inflamed pulp is incapable of healing based on subjective and objective criteria. Several treatment methods have been proposed, such as pulpotomy which involves the removal of the more intensely inflamed pulpal tissues to the level of the canal orifices and the subsequent placement of a biocompatible pulp capping material following bleeding control. In other cases, inflammation is more widespread and requires thorough endodontic therapy and total pulpal tissue excision. (Garg and Garg, 2019; Neelakantan et al., 2020).

Pain control in the early treatment stages can critically enhance patient and dentist confidence. Local anesthetic use alone is less effective in SIP pain management. Inadequate pain control during treatment is one of the leading factors in central and peripheral sensitization, which may result in more significant pain during recovery (Fried and Gibbs, 2014). The most common medications in pain relief are non-steroidal anti-inflammatory drugs (NSAIDs) (SACHS, 2005). Pre-treatment with NSAIDs decreases pain perception during endodontic treatment (Van Wijk and Hoogstraten, 2006). It also promotes the success rate (39 %) of inferior alveolar nerve block in teeth with SIP because NSAIDs decrease nociceptor activation by lowering the levels of inflammatory mediators (Abbott and Paul Abbott, 2022).

Removal of pulpal inflamed tissues eliminates endodontic pain (Kumar et al., 2014). However, the frequency of post-endodontic pain is reported to vary between 3 % and 58 % (Sathorn et al., 2008). Microbiological, chemical, and mechanical insults to peri-radicular tissue exacerbated by root canal therapy are regarded as potential sources of post-operative discomfort (Ince et al., 2009, Sathorn et al., 2008).

Diclofenac potassium (DP) is one of the most effective and commonly used analgesics for dental pain (Gazal and Al-Samadani, 2017). It shows a significant decrease in post-operative pain as an oral pre-treatment due to its anti-inflammatory, analgesic, and antipyretic action. It acts mainly via inhibiting cyclooxygenase (COX 1 and COX 2) enzymes, leading to inhibition of prostaglandin synthesis (Isola et al., 2019). COX 1 participates in platelet action, protection of stomach mucosa, and kidney function. Its inhibition by NSAIDs is the reason for the cardiovascular, renal, and upper gastrointestinal side effects reported to be raised with increased doses and frequency of NSAIDs administration (Altman et al., 2015, L.J., 2013).

Altman et al. described the application of pharmaceutical technology in minimizing the side effects of diclofenac, one of the most efficient and widely used NSAIDs. Among the discussed pharmaceutical techniques is topical application at the site of inflammation, if accessible, through a suitable formulation that allows the drug to permeate the inflammatory tissues. Its attraction and accumulation at the inflammatory sites, where COX2 inhibition occurs, explain the extended duration of action that exceeds its plasma half-life (Altman et al., 2015, L.J., 2013).

The low acidic environment of the inflamed tissues reduces the binding of plasma proteins, thereby increases the free drug fraction and facilites drug diffusion to the intracellular spaces where the therapeutic effect occurs (Altman et al., 2015, L.J., 2013).

NSAIDs applied topically at the site of inflammation achieve only 3–5 % of the total systemic absorption compared to oral products. Meanwhile, its concentration in inflamed tissues is higher compared to oral administration (Brunner et al., 2005). It was also reported that peak plasma levels following topical use were less than 10 % of those achieved after oral intake (Heyneman et al., 2000). Most studies comparing oral versus topical use of diclofenac reflect comparable clinical efficacy with minimal side effects for topical rout (v.Tieppo et al., 2017). Accordingly, lower circulating diclofenac levels following topical application were shown to significantly lower gastrointestinal adverse effects following oral administration (6.5 % versus 23.8 %), even after prolonged treatment (Simon et al., 2009). Consequently, the American College of Rheumatology and the American Academy of Orthopedic Surgeons guidelines recommend the application of topical NSAIDs for osteoarthritis of the hand or knee, especially in old age and patients with gastrointestinal problems (Academy et al., 2008, Hochberg et al., 2012, Jevsevar, 2013, Stanos, 2013). It is more serious for many renal patients. Even a single oral dose of diclofenac could be detrimental in patients with underlying chronic kidney disease (CKD) or pre-existing subclinical acute kidney injury (AKI) (Hellmsa et al., 2019, Klomjit and Ungprasert, 2022, Rosik et al., 2021, Störmer et al., 2022). Elderly patients and those with comorbidity factors e.g congestive heart failure, liver cirrhosis, or CKD may develop acute renal failure (ARF) upon oral administration of NSAIDs.

NSAIDs use is a risk factor for contrast induced nephropathy (CIN) mostly defined as a relative increase in serum creatinine by ≥25 % or glomerular filtration rate (GFR) by ≥25 % within 24 to 72 h after contrast media exposure. CIN is a common complication in high risk patients such as those with CKD and diabetes mellitus (Hörl, 2010).

Additionally, oral diclofenac has only 50 % bioavailability because of its extensive first-pass effect. (L.J., 2013). The transmucosal route offers unique benefits over the oral route, like bypassing the hepatic first-pass effect, which decreases the dose and dosing frequency and reduces fluctuation in steady-state levels.

Mucoadhesion to the gingiva at the site of the endodontic procedure shows much more beneficial passive targeting of DP that is known to accumulate at the inflamed tissues, exerting a localized effect that diminishes systemic side effects (Averineni et al., 2009, Pipalia et al., 2016). Bioadhesion to the gingival mucosa minimizes systemic absorption (Patel et al., 2011, Razzaq et al., 2021) and consequently, side effects (Abbott and Paul Abbott, 2022). Moreover, targeting inflamed tissues allows the possibility of dose reduction, which further minimizes side effects (Esim et al., 2020, Jin et al., 2023, Raghavendra Rao et al., 2013).

Some research has been conducted using drugs in bioadhesive mucosal patches to evaluate their efficacy (Annigeri et al., 2015, Pipalia et al., 2016). However, the examination of DP transmucosal bioadhesive disc efficacy in managing intra- and postoperative endodontic pain was not previously reported. The transmucosal bioadhesive disc formulation is advantageous in its simple, easy, and inexpensive scaling up.

This study aimed to introduce a mucoadhesive buccal disc of DP to be applied to the gingiva at the site of dental pain or inflammation. Sealing the outer surface allows unidirectional, accurate dose delivery at the application site. The mucoadhesive surface allows intimate contact with the mucosa, enhancing permeation to the targeted inflammatory tissues where the drug persists and exerts its action.

Our goal was to minimize side effects and enhance the anti-inflammatory efficacy of DP in dental pain through passive targeting of the inflamed tissues, and to halve the conventionally used dose. The introduced 25 mg bioadhesive gingival disc was evaluated in patients with SIP in a randomized clinical trial. The effectiveness of inferior alveolar nerve block as well as intra- and postoperative pain reduction were tested after a single-dose pre-medication with the prepared bioadhesive disc compared with the conventionally used 50 mg marketed oral tablet of DP.