Achieving profound pulpal anaesthesia during endodontic treatment, particularly in mandibular molars with symptomatic irreversible pulpitis (SIP), remains a persistent clinical challenge. Inferior alveolar nerve block (IANB), although routinely employed, demonstrates a high failure rate in such cases, with reported success rates ranging from 19 to 56% owing to the heightened inflammatory state of the pulp (1,2).

Achieving effective anaesthesia in cases of SIP in the mandibular molars, particularly with an IANB, is challenging due to a combination of physiological and anatomical factors. Severe inflammation in SIP releases mediators, such as prostaglandins and bradykinin, which sensitize pulpal nociceptors, lowering the pain threshold and causing hyperalgesia. This makes the nerves hyper-responsive, reducing the efficacy of local anaesthetics (3). Additionally, the acidic environment in inflamed tissues lowers the pH level, hindering the dissociation of anaesthetics, such as lidocaine, into their active form, thus impairing nerve membrane penetration and sodium channel blockade. Inflamed nerves may also express more sodium channels, which further resisting anaesthesia (4). Anatomically, mandibular molars pose challenges owing to potential accessory innervation from nerves, such as the mylohyoid, lingual or long buccal nerves, which may not be fully blocked by a standard IANB (3). Collectively, these factors make profound anaesthesia difficult to achieve in patients with SIP.

Several strategies have been explored to improve anaesthetic outcomes, including supplemental techniques (intraosseous, intraligamentary and buccal infiltrations) and the use of different anaesthetic agents or volumes (5). While a considerable success rate has been documented for intraosseous injections, this technique not only requires specialized apparatus, but also incurs significant expenses and has the potential to inflict damage on root structures, induce systemic complications, provoke pain and result in post-injection discomfort (6). Intrapulpal injections are associated with significant pain and require pulp exposure (5).

Cryotherapy, a non-pharmacological modality involving the application of cold, is a promising adjunctive strategy. It induces local vasoconstriction, reduces oedema, reduces nerve conduction velocity and elevates the pain threshold through nociceptor desensitization (7). However, the potential risks associated with cryotherapy, such as transient tissue sensitivity or discomfort from cold application, should be considered, although these are typically minimal with controlled application (7). Previous studies have demonstrated that intraoral cryotherapy can improve the success rate of IANB, and reduce intraoperative and post-operative pain during endodontic procedures (7-10). For instance, Gopakumar et al (11) evaluated the anaesthetic efficacy of Endo-Ice spray and intrapulpal ice sticks as adjuncts to IANB in patients with SIP, finding that both methods significantly reduced pain and improved anaesthesia success, with ice packs exhibiting superior outcomes. Moreover, mechanistic investigations have demonstrated that cooling can suppress capsaicin-sensitive pain receptors and modulate inflammatory pathways, offering a plausible biological rationale for its analgesic effects in inflamed pulp tissues (7,8).

Although previous studies have separately investigated buccal ice packs or intrapulpal ice application as adjuncts to IANB (9,10), the combined use of surface and intrapulpal cryotherapy to maximize analgesic efficacy in patients with SIP has not yet been explored in a single randomized controlled trial (RCT), at least to the best of our knowledge. The present study aimed to address this gap by evaluating the efficacy of cryotherapy as a supplemental aid to IANB in patients with SIP undergoing endodontic treatment, with the primary outcome being the anaesthesia success rate (defined as no or mild pain during treatment), and the secondary outcome being pain scores during access opening and cleaning/shaping. By providing a non-invasive, chairside approach to enhance anaesthesia and reduce pain, cryotherapy holds significant clinical relevance for improving patient comfort and procedural outcomes in endodontic practice, particularly for challenging SIP cases. The null hypothesis was that cryotherapy would not enhance IANB efficacy compared with conventional IANB alone.

The CONSORT flow diagram is presented in Fig. 1. The study results demonstrated the baseline comparability (Table I) of group I and group II, with the mean ages of the patients being 32.8±6.20 and 32.6±6.31 years, respectively (P=0.9), and a non-significant sex distribution, with each group consisting of 15 males (25%) and 15 females (25%).

The pre-operative pain scores were similar between the groups (99.17±15.57 vs. 95.33±18.56, P=0.39) (Table II). This demonstrated that both groups were comparable at baseline. Group II exhibited significantly lower pain during access opening compared with group I (20.60±29.90 vs. 41.43±43.10, P=0.03), although not during cleaning and shaping (17.73±24.06 vs. 26.95±36.72, P=0.27) (Table II). Intragroup analysis via repeated measures ANOVA confirmed a significant pain reduction over time in both groups (Table III). Post hoc analysis with the Bonferroni test revealed significant pain reductions from preoperative to access opening and cleaning/shaping in both groups (P=0.0003), with greater reductions in group II (Table IV), but no notable difference between cleaning/shaping and later stages. The overall anaesthesia success rate was higher in group II (79.3%, 23/29) than in group I (65.3%, 17/26) (P=0.247), indicating that cryotherapy enhanced IANB efficacy in patients with SIP; however, this difference between the groups was not significant (Table V).

Effective pain management remains the cornerstone of successful endodontic therapy, with the ability to achieve profound anaesthesia, often serving as a critical measure of clinical competence. IANB is the gold standard for anesthetizing mandibular teeth during endodontic procedures. However, achieving adequate anaesthesia in teeth with SIP presents a significant challenge owing to the acute inflammatory state of the pulp. Inflammation in SIP leads to an increased expression of tetrodotoxin-resistant sodium channels on nociceptors, which are less responsive to local anaesthetics, reducing the success rate of IANB by up to eight-fold (18). This physiological barrier, combined with other factors, such as patient anxiety, inaccurate injection techniques and anatomical variations, has prompted the exploration of supplementary methods to enhance the efficacy of IANB (5). Despite these efforts, no technique has achieved complete pulpal analgesia, underscoring the need for innovative approaches to improve pain control during endodontic treatments.

The present study utilized a volume of 3.6 ml of 2% lidocaine for IANB, based on the findings presented in the study by Aggarwal et al (19), who reported a higher success rate with this dosage compared to 1.8 ml in patients with SIP and reported similar success rates with 2% lidocaine, 4% articaine and 0.5% bupivacaine. This choice of anaesthetic volume aligns with the aim of the study of optimizing the efficacy of IANB as a baseline for comparison with cryotherapy. Cryotherapy was administered to the experimental group (group II) using a combination of refrigerant spray (Endo-Frost, Coltene) and intrapulpal ice sticks. Cryotherapy has been explored in endodontics in various forms, including cold saline irrigation and intraoral ice packs, with evidence suggesting that it can mitigate postoperative pain and enhance anaesthetic outcomes (9,20). For instance, it has been demonstrated that cold saline irrigation significantly reduces postoperative pain in teeth with vital pulps, likely by reducing inflammation and pulpal nerve activity (21).

In the present study, group II (cryotherapy) demonstrated significantly lower mean pain scores than group I (control) during access opening (P<0.001), indicating that cryotherapy effectively enhanced the efficacy of IANB at this stage of treatment. However, during cleaning and shaping, while group II exhibited a lower mean pain score, the difference was not statistically significant (P>0.05). This non-significant difference may be attributed to the transient nature of the analgesic effects of cryotherapy, as the cooling-induced nociceptor desensitization and reduced pulpal blood flow likely diminish over time (7). The intrapulpal ice application, administered for 4 min immediately following access cavity preparation, may have exerted its maximum effect during the initial stages of treatment, with the cryoanesthetic effect waning by the time cleaning and shaping commenced, typically 10-15 min later in the procedure. This temporal limitation is consistent with prior studies, such as Vera et al (22), which noted that the effects of cryotherapy are most pronounced within a short window post-application due to tissue rewarming and restoration of normal neural conduction. Additionally, the mechanical stimulation and irrigation during cleaning and shaping may further activate sensitized nociceptors in inflamed pulp tissue, potentially counteracting the residual cryotherapy effect (21). These factors likely explain the lack of a significant difference at this later stage, suggesting that supplemental cryotherapy applications or alternative adjunctive techniques may be necessary to maintain analgesia throughout the entire endodontic procedure.

The present study experienced a higher dropout rate in the control group (4 patients) compared with the experimental group (1 patient), primarily due to anaesthesia failure, raising the possibility of skewed outcomes. However, the use of an ITT analysis, alongside the primary per-protocol analysis of completers (26 control and 29 experimental patients), helped mitigate potential bias by including all randomized participants in the final analysis.

Cryotherapy induces vasoconstriction and diminishes cellular metabolism by restricting biochemical processes, which reduces the extent of tissue injury, consequently reducing the oxygen requirements of cells and curtailing the production of free radicals within tissues. The vasoconstrictive response yields anti-edematous effects, whereas analgesia is attained following a decrease in temperature due to the inhibition of nerve endings resulting from the application of cold stimuli (7). The magnitude of the vasoconstriction reaches its peak at a temperature of 15˚C, and research has indicated that a reduction in body temperature diminishes peripheral nerve conduction; notably, at ~7˚C, there is a total deactivation of myelinated A delta fibres, whereas the non-myelinated C-fibres become inactive at ~3˚C (23).

Overall, in the present study, group II achieved a higher success rate of anaesthesia than group I, with a statistically significant difference. These findings are consistent with those of Topçuoğlu et al (24), who reported that preoperative intraoral ice pack application for 5 min significantly improved IANB success rates in patients with SIP. Similarly, Gopakumar et al (11) evaluated the effect of intraoral cryotherapy using ice sticks and refrigerant spray, and found that both methods significantly reduced pain and improved IANB outcomes in SIP cases, with ice packs showing superior results, as observed in the present study.

The application of Endo-Frost refrigerant spray (-50˚C), composed of propane, butane and isobutane, in combination with intrapulpal ice sticks for 4 min, likely contributed to the observed pain reduction in group II. Vera et al (22) suggested that the optimal duration of cryotherapy varies by tissue type, with 4-5 min being sufficient to achieve therapeutic effects without causing damage in areas with minimal muscle and fat, as in intraoral applications. The 4-min duration for intrapulpal ice application used in the present study was selected based on this evidence, as it balances the need for effective nociceptor desensitization and reduced pulpal blood flow with the prevention of thermal injury to pulpal or surrounding tissues. This duration is further supported by practical considerations, as preliminary testing indicated that 4 min allowed consistent cooling of the pulp chamber without patient discomfort or procedural delays, aligning with findings from Gopakumar et al (11), who used a similar duration for intrapulpal ice application. By contrast, Koteeswaran et al (25) found no significant difference between IANB alone and IANB with cryotherapy using Endo-Ice spray (-26.2˚C) and intrapulpal ice. This discrepancy may be attributed to the lower temperature of Endo-Frost (-50˚C) used in the present study, which likely produced a more pronounced cryoanesthetic effect compared to Endo-Ice, facilitating deeper tissue cooling and greater pain reduction.

The physiological mechanisms of cryotherapy provide the rationale for its effectiveness. Cold application extracts heat from the tissue, causing vasoconstriction and reducing local inflammation, thereby mitigating oedema and inflammation (7). Goodis et al (26) reported that tooth cooling decreased pulpal blood flow, which can eliminate pain perception in some cases. Additionally, cryotherapy reduces the adherence of leukocytes to capillary endothelial walls and decreases endothelial dysfunction (7). According to Van't Hoff's law, a 10˚C decrease in tissue temperature reduces local enzyme activity and cellular metabolism by 2-3-fold, minimizing tissue damage (7). Furthermore, cryotherapy disrupts nerve conduction by causing myelin sheath deterioration and axonal degeneration, raising the nociceptive threshold, and slowing pain signal transmission (19). Cold also inactivates oral vanilloid receptors, which are upregulated during inflammation and are sensitive to capsaicin, further reducing pain perception (27). These mechanisms likely explain why patients often use cold (e.g., ice or cold water) to alleviate acute pulpal pain, a clinical observation supported by prior literature (28,29). Collectively, these factors likely contributed to the significant pain reduction observed in group II compared with group I during endodontic treatment.

Demographic variables (pre-operative pain, age and sex) were comparable between the two groups, indicating that these factors did not influence the study outcomes. Consequently, the null hypothesis that there would be no difference in IANB efficacy between group I and group II was rejected. The superior performance of the cryotherapy group underscores its potential as a non-invasive, chairside technique to enhance IANB efficacy in SIP cases.

Previous studies evaluating cryotherapy as an adjunct to IANB in patients with SIP have provided valuable insight, but are not without potential biases (9,11,15). A number of studies, including those examining buccal ice packs or intrapulpal ice application, often faced challenges with blinding due to the sensory nature of cold application, which may introduce placebo effects or patient reporting bias, particularly when subjective pain scales like the Heft-Parker VAS were used (11,30). Additionally, small sample sizes in some trials may have limited statistical power, potentially overestimating or underestimating the efficacy of cryotherapy. Variability in patient selection criteria, such as inconsistent preoperative pain thresholds or inclusion of patients with differing levels of dental anxiety, could further confound results, as these factors influence pain perception and anaesthesia outcomes (15,31). These methodological limitations highlight the need for more robust study designs, such as larger sample sizes and the use of sham cryotherapy or objective pain assessment methods, to minimize bias and enhance the reliability of findings in future research.

The findings of the present study suggest several clinical implications for integrating cryotherapy into the management of SIP in endodontic practice. First, cryotherapy, using a combination of cold spray and intrapulpal ice application, can serve as an effective adjunct to inferior alveolar nerve block anaesthesia, particularly for patients with severe pre-operative pain. This approach enhances patient comfort during initial treatment stages, potentially improving procedural efficiency and patient cooperation in challenging cases. Second, in settings where immediate root canal therapy is not available, such as emergency departments or rural clinics, cryotherapy could provide temporary pain relief by reducing pulpal inflammation and nerve sensitivity, acting as a bridge to definitive treatment while referrals are arranged. Third, by decreasing inflammation and nerve responsiveness, cryotherapy may help reduce post-operative pain, potentially lowering the need for analgesics and supporting a smoother recovery. Incorporating cryotherapy into standard protocols for managing symptomatic irreversible pulpitis offers a non-invasive, cost-effective strategy to improve anaesthesia outcomes and patient experience. However, further research is required to establish standardized protocols, including optimal timing and frequency of cryotherapy application, to ensure consistent benefits across diverse clinical settings.

Despite these promising results, the present study has several limitations. The small sample size (n=60) may limit the generalizability of the findings, necessitating larger trials to confirm the efficacy of cryotherapy. Additionally, the lack of blinding for both operators and patients due to the nature of cryotherapy application introduces a potential for bias, which could have influenced pain reporting. Future studies could mitigate this limitation by implementing sham cryotherapy, such as using a non-cooled spray or room-temperature sticks, to blind participants and operators while maintaining the procedural appearance of cryotherapy application. Additionally, employing objective pain assessment methods, such as pulpal nerve stimulation or physiological monitoring (such as heart rate variability), could further reduce bias in pain reporting. Variations in operator skill during cryotherapy application or differences in pulp chamber anatomy across patients may have also influenced the consistency of the effects of cryotherapy, as these factors could affect the precision of ice stick placement or the extent of cooling achieved. These strategies would enhance the robustness of future trials evaluating the efficacy of cryotherapy in endodontic pain management.

In conclusion, cryotherapy, as a supplementary technique, significantly enhances the efficacy of IANB in patients with SIP, particularly during access opening, offering a simple and non-invasive method to reduce pain and improve patient comfort. The higher anaesthesia success rate compared to conventional IANB alone underscores its potential as a valuable adjunct in endodontic practice. However, larger, well-controlled studies are required to validate these findings and address the limitations of the present study, ensuring the consistent integration of cryotherapy into standard protocols for managing SIP.