Comparing Etizolam and Music Distraction on Inferior Alveolar Nerve Block Success in Patients With Symptomatic Irreversible Pulpitis: A Randomized Clinical Trial

Inferior alveolar nerve block (IANB) is a standard technique for achieving local anesthesia for endodontic treatment in mandibular teeth. However, in cases of symptomatic irreversible pulpitis (SIP), IANBs have a high failure rate ranging from 15% to 39%.^1–3 Various factors responsible for this reduced anesthetic success include pulpal inflammation, anatomical variations, acute local anesthetic tachyphylaxis, tetrodotoxin-resistant sodium channels, and psychological factors such as anxiety and fear.¹ Patients with SIP are often already anxious and actively experiencing pain, and the anticipation of added pain during endodontic therapy further elevates their nervousness.^4,5 During endodontic therapy, anxious patients report more intraoperative pain as compared to those having less dental anxiety.^6,7 Therefore, it is imperative to manage dental anxiety to effectively manage pain during endodontic treatment.

Different methods have been suggested to control anxiety in the dental office, which can be divided broadly into pharmacological or nonpharmacological approaches.^8,9 There are several pharmacologic options, including benzodiazepines (BZDs) which are common antianxiety drugs used in dental offices.⁸ Different oral surgical studies have observed higher anxiolytic activity and improved IANB success after preoperative administration of BZDs like triazolam, oxazepam, and chlordiazepoxide.^10,11 However, other clinical studies employing preoperative BZDs to enhance local anesthetic success have reported mixed findings. Some endodontic intervention studies reported no effect from preoperative alprazolam or triazolam on improving local anesthetic success.^12–14 In contrast, another study found significantly higher IANB success with a preoperative combination of alprazolam and diclofenac potassium.¹⁵

Major side effects that preclude frequent use of BZDs in dental offices are their sedative and dependence effects. Etizolam, a thienodiazepine, is a BZD analogue which acts by facilitating the inhibitory effects of GABA like BZDs but has a weak affinity for GABA receptors containing α1 subunits and thus has lower sedative effects compared to BZDs.¹⁶ A recent crossover trial has shown that 0.25 and 1 mg doses of etizolam had no significant effects on vigilance, short-term memory, psychomotor coordination, or speed in decision-making.¹⁷ Etizolam is used in Japan, Korea, Italy, and India but is not approved for medical use in the United States.¹⁸ To our knowledge, no endodontic study has evaluated the role of etizolam in improving the IANB success in anxious patients.

Nonpharmacological interventions to reduce dental anxiety include audio analgesia, aroma therapy, brief relaxation, hypnosis, and counselling.^19,20 Audio analgesia or music distraction (MD) is a commonly used noninvasive technique for anxiety reduction in which the subject listens to pleasant music during treatment. Different restorative and endodontic studies have shown that listening to music during treatment resulted in decreased anxiety scores^19,21 and improved physiological parameters like a decrease in heart rate and blood pressure²⁰ as well as an increase in finger temperature.²¹ However, whether this decreased anxiety translates to reduced intraoperative pain during endodontic treatment remains unexplored. To our knowledge, only 1 endodontic study investigated the effect of MD on intraoperative pain and reported that patients who listened to music experienced significantly less pain during endodontic therapy,²² but they did not specify the type of local anesthesia or the pulpal status of the teeth undergoing endodontic treatment.

No endodontic study has yet compared the effect of anxiolytic medication and music distraction on reducing intraoperative pain during endodontic therapy. Hence, this study was performed to assess the influence of preoperative etizolam vs MD on IANB success in anxious patients during endodontic therapy of mandibular molars diagnosed with SIP. This study also aimed to compare intraoperative pain during endodontic treatment of symptomatic mandibular molars under the influence of preoperative etizolam or MD in highly anxious patients.

METHODS

This randomized clinical trial was developed in accordance with CONSORT guidelines (Figure). This was a parallel, randomized, placebo-controlled study with a 1:1 allocation ratio and was conducted in the Postgraduate Department of Conservative Dentistry and Endodontics, JCD Dental College, Sirsa (Haryana), from November 2020 to July 2022. Ethical clearance was obtained from the Institutional Ethics Committee, and the study was registered with the Clinical Trials Registry. Informed consent was obtained from all patients included in the study.

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Inclusion criteria were as follows: patients who were healthy (American Society of Anesthesiologists [ASA] category 1), aged 18 to 60 years, and who had a mandibular first or second molar diagnosed with SIP. Only highly anxious patients (determined by the modified Corah Dental Anxiety Scale)²³ having moderate to severe pain (as determined by Heft Parker Visual Analog Scale)²⁴ were included in the study. Diagnosis of SIP was made based on symptoms of spontaneous/lingering pain, confirmed by application of cold spray (Endo-Frost, Roeko) and absence of any radiographic periapical changes. Patients were excluded if they were unable/unwilling to provide consent, allergic to etizolam, the local anesthetic, or any of its components, pregnant, lactating, immunocompromised or medically compromised, drug abusers or alcoholics, or if they had active pathology in the injection area, a sleep disorder, severe liver impairment, or depression.

A modified Corah Dental Anxiety Scale (MDAS) was used to assess anxiety levels of all patients.²³ For better patient understanding, MDAS was framed in English and Hindi languages. It covered 5 question areas using a simplified 5-point scale that ranged from 0 (not anxious) to 5 (extremely anxious). The total anxiety score was calculated by adding the responses from each of the questions, producing a total range of 5 to 25. A score of 12 or above indicated high dental anxiety, and a score of more than 19 was considered possibly dental phobic. Only patients with MDAS scores of 12 and above were included in the present study.

Throughout the study, the Heft-Parker Visual Analogue Scale (HP-VAS) was used to assess pain as reported by the patients.²⁴ This is a 170-mm scale divided into 4 categories: no pain (0 mm), mild pain (1–54 mm), moderate pain (55–114 mm), and severe pain (115–170 mm). Pain intensity was evaluated by asking the patient to place a mark on the scale with readings from 0 to 170 mm. All patients were properly educated about HP-VAS markings before recording their pain. Only patients with moderate to severe preoperative pain (≥55 mm) were included in the study.

All included patients were randomly allocated to a respective group using a sealed envelope system prepared by a trained assistant who was not part of the study. Patients selected an envelope and were allocated accordingly to Group P (placebo), Group MD, or Group E (etizolam). The preoperative medications (placebo or etizolam) were identical in shape and size and were administered to the patient by the same research assistant 60 minutes before administering the local anesthetic. A 4-number code was also assigned to each patient. This code was transferred to the patient data sheet by operator and not broken until study completion. Therefore, both the patient and operator were blind to Groups P and E.

All clinical procedures were performed by a single operator (HS). Patients in Groups P and E orally consumed identically appearing tablets containing either lactose or etizolam (0.5 mg), respectively. Before giving the placebo/etizolam tablet, we confirmed that the patients were accompanied by a responsible person, otherwise the patient was excluded from the study. Sixty minutes after taking the tablet, patients received a standard IANB with 1.8 mL of 2% lidocaine with 1:200,000 epinephrine. Patients in the MD group listened to their favorite music through wireless headphones (JBL T460BT, Harman) just before receiving the local anesthetic injection. They continued to listen to self-selected music at their preferred volume throughout the entire endodontic procedure. Patients in the other 2 groups did not wear headphones.

Fifteen minutes after the injection, patients were assessed for lower lip numbness. In patients with lip numbness, the involved tooth was then isolated using a rubber dam and endodontic access was initiated. After dentin penetration and deroofing of the pulp chamber, canal orifices were located with an endodontic explorer and stainless-steel K-files were used for initial instrumentation of the root canals. Patients who did not report lip numbness or exhibited no bleeding from pulp chamber were excluded from the study. In all groups, patients were asked to report pain occurring anytime during the endodontic procedure and then assessed using the HP-VAS scale. No or mild pain (0–54 mm) was counted as success, whereas moderate to severe pain (55–170 mm) during the procedure was considered failure of IANB. Pain was not assessed after local anesthetic delivery. Pain was only recorded preoperatively and during the procedure. If patients never reported any pain during the endodontic treatment, they were assessed using HP-VAS after pulp extirpation. All failure cases were managed using supplemental local anesthesia techniques in the same or subsequent visits, but their data were not included.

RESULTS

A total of 220 patients were initially recruited for the study; however, 90 patients did not meet the inclusion criteria, and 20 patients declined to participate. The remaining 110 patients were randomized into the following: Group P (n = 35), Group MD (n = 36), and Group E (n = 39). Four patients were excluded from Group P (1 failed to show for treatment, and 3 did not report lip numbness), 5 were excluded from Group MD (3 found wearing headphones uncomfortable, and 2 failed to report lip numbness), and 8 patients were excluded from Group E (4 were not accompanied by a responsible adult, 2 failed to show for treatment, and 2 did not achieve lip numbness). Therefore, a total of 93 patients (31 in each group) completed the trial and were statistically analyzed (CONSORT Flow Chart; Figure).

No significant differences were detected between any of the groups regarding age, sex, tooth type, or mean preoperative pain and anxiety scores (P > .05; Table 1). According to the preoperative MDAS scores, no patient fell within the dental phobic category (>19) in this study.

Table 1.Demographic Data and Initial Pain and Anxiety Scores

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Regarding local anesthetic success, 21 patients (67.7%) in the MD group exhibited success, while only 5 (16.1%) and 11 (35.5%) exhibited success in Groups E and P, respectively. Patients belonging to MD group demonstrated significantly higher anesthetic success than Groups E (P < .001) or P (P = .011). However, no significant difference was found in IANB success rates between Groups P and E groups (P = .073; Table 2).

Table 2.Comparison of Group Inferior Alveolar Nerve Block (IANB) Success Rates and Intraoperative Pain Scores

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Patients in the MD group exhibited significantly less intraoperative pain than those in Group E (P < .001) or Group P (P = .004). However, there was no significant difference in intraoperative pain scores between Groups E and P (P = .197; Table 2).

DISCUSSION

Endodontic treatment is a major anxiety-provoking factor for dental patients.²⁵ Clinical evidence suggests that anxious patients report more pain during endodontic therapy. This randomized clinical trial was designed keeping in mind that alleviating a patient’s anxiety with medication or music may result in lower intraoperative pain or, in other words, enhanced local anesthetic success. The present study found music distraction to be significantly more effective than etizolam for increasing the IANB success rate in symptomatic molars.

The promising results of music can be due to the anxiolytic effects of music and its physiologic effect on the brain, where it downregulates structures (eg, the amygdala or hippocampus) that are associated with negative responses, activates the reward system, and maximizes pleasure.²⁶ Music has a strong influence on the amygdala; a part of the limbic system that releases endorphins and regulates the emotional processes.²⁷ Endorphins are neuropeptides produced in the brain that serve to combat the effects of physiological and psychological stress. Additionally, endorphins, particularly β endorphins, have potent analgesic effects.²⁸ In an exclusive study evaluating the effects of music, healthy volunteers who listened to music reported an increase in pressure pain thresholds and a decrease in pain scores with mechanical pin pricking and temporal summation of pain.²⁹

The type of music plays an important role in patient behavior modification. Different forms of music have been employed to alleviate patient’s anxiety.^30,31 One clinical trial employed music at a frequency of 432 Hz and observed decreased anxiety in patients undergoing endodontic treatment.²⁰ Music at 432 Hz, characterized by its slow rhythms and melodies, has the unique ability to induce physical and emotional relaxation in listeners.²⁰ Further, this frequency aligns most with natural human frequencies,³² and its neutrality frees the music from any emotional triggers that could lead to physiological responses in patients, providing a sense of reassurance.

Meyer stated that to generate a calm atmosphere, the most suitable form of music is the patient’s own preferred music.³³ Different medical studies validated that listening to preferred music provides pleasure and intense euphoric feelings by releasing neurotransmitters like dopamine and providing endogenous opioid-mediated responses and analgesia.^34–36 Patients in our study listened to their preferred playlist with full volume control during the entire endodontic therapy. In this manner, the patient’s exposure to noxious or unpleasant sounds in the dental operatory was minimized, which is considered a major source of patient anxiety.³⁷ It was interesting to observe that some patients increased the music volume as soon as the dental handpiece was operated. Conversely, there are few pediatric studies where, regardless of choice, music failed to attain significant anxiolysis^30,38 or pain control.³⁰ In these studies, most of the enrolled children had low preoperative anxiety scores, and therefore, further improvement in their scores due to music was unlikely. Also, participants in these trials received routine restorative dental care (not endodontic treatment) which was likely less traumatic or pain-provoking. Nevertheless, most patients appreciated the music and chose to listen to it in subsequent appointments.³⁰

In our study, etizolam as a preoperative oral anxiolytic did not improve IANB success. Our study was the first to use preemptive etizolam to enhance anesthetic success. Due to its affinity for specific GABA-A receptors associated with anxiety, etizolam has pronounced antianxiety effects.³⁹ However, whether etizolam alleviated patient anxiety in the present study remains unknown as we did not reevaluate anxiety scores before initiating endodontic treatment. Interestingly, our study found that placebo was associated with a higher rate of anesthetic success than etizolam, although the difference was nonsignificant. The exact mechanisms of placebos are not fully understood, but they involve a complex neurobiological response that includes increased levels of neurotransmitters like endorphins and dopamine as well as greater activity in brain regions related to mood and self-awareness.

The current study observed an overall anesthetic success rate of merely 40%, which was markedly lower than the findings reported in the previously mentioned studies,^1–3 particularly for Groups P and E. This probably happened because we only included highly anxious patients. The diminished anesthetic success observed in our study suggests the potential influence of anxiety on pain perception during endodontic therapy.

To improve IANB success in mandibular molars with SIP, 2 endodontic intervention studies utilized preoperative sublingual/oral triazolam¹⁴ or alprazolam¹³ but failed to demonstrate enhanced local anesthetic success. In both studies, postmedication anxiolysis was not evaluated. However, in a previous study, despite exhibiting marked decreases in anxiety, patients who consumed triazolam before endodontic treatment experienced pain scores similar to placebo.¹² The findings of these studies and the current study suggest that minimal to moderate sedation is not a singularly reliable method of achieving adequate pain control/successful local anesthesia. Despite achieving significant anxiolysis, sedated patients may still respond to pain during endodontic treatment if local anesthesia is unsuccessful.

Another possible reason for diminished local anesthetic success in Group E could be the long waiting time. When prescribed orally, etizolam has an onset of 30 to 60 minutes. Therefore, after consuming etizolam, patients waited one hour before treatment. It has been demonstrated that lengthier waiting times are significantly associated with anxiety.⁴⁰ Though we did not reassess anxiety, all patients in our study were emergency patients, had moderate to severe dental pain, and exhibited heightened anxiety, all of which could have worsened because of the extended waiting time with etizolam and caused decreased IANB success. On the other hand, patients allocated to the MD group received local anesthetic injections and endodontic treatment much quicker than those in the other 2 groups, which could have influenced the results.

The findings of our study do not corroborate with 1 study which obtained higher local anesthetic success when patients were premedicated with a combination of an anxiolytic (alprazolam) and an analgesic (diclofenac potassium).¹⁵ These findings could be attributed to the use of diclofenac which might have influenced the pain perception of endodontic patients.

The side effects of etizolam include drowsiness, sedation, and slurred speech.^41,42 Out of 31 patients, 12 in Group E felt drowsy during the endodontic procedure, and 2 patients almost fell asleep in the dental chair. Considering this fact, only patients accompanied by a responsible person were included in the trial. Etizolam is contraindicated in patients having sleep disorders, severe liver impairment, depression, hypersensitivity, drug abusers, and alcoholics.⁴² To avoid any risk of adverse effects, a thorough medical history was obtained from all patients before administering etizolam. Further, patients were instructed to contact the operator in case of any drug-related adverse effects. However, none of the patients reported any adverse effects of etizolam after treatment.

In dentistry, different multiple and single item self-reporting questionnaires are used to evaluate dental anxiety in patients. The most common questionnaires are the Corah’s Dental Anxiety Scale, Modified Corah Anxiety Scale (MDAS), and dental fear survey.⁴³ The present study employed MDAS because of its simplicity, ease of translation into English and Hindi (the native languages of our patients), and its reliability for measuring preoperative anxiety. Moreover, the MDAS has an additional focus on local anesthesia, which is not considered in original Corah anxiety scale.²³

We also assessed preoperative and intraoperative pain levels using the HP-VAS because it is reliable, reproducible, scientifically valid, and easily understood by patients.²⁴

Our study employed strict inclusion criteria, where only highly anxious patients were included. To reduce heterogenicity, only mandibular molars with SIP were selected. To eliminate operator and environmental bias, a single operator treated all patients. However, the operator was not blinded since patients in Groups P and E did not use headphones during treatment. Moreover, there was a difference in timing between the P and E groups and the MD group, which may have eroded the blinding of the patient and operator. A more thorough study design would involve having patients wear headphones without any music being played and having the MD group also take a placebo tablet, plus having all patients wait the same amount of time. In addition, some patients who consumed etizolam felt drowsy, which may have led the operator to suspect their group assignment.

We did not measure the postoperative anxiety levels since the sole purpose of our study was to evaluate IANB success. However, measuring anxiety levels might have helped us to know if etizolam or MD actually reduced patient anxiety. All patients in Group E were given a standard dose of 0.5 mg; however, a customized mg/kg dose may have provided better results. In the present study, no patient was dental phobic (MDAS > 19), so the results may be applicable only to highly anxious patients. Furthermore, nonanxious patients were not included in our study, so it is difficult to say whether the same results would occur in patients without severe anxiety. Future studies are needed to test whether anxiety causes patients to react and report pain when there is none, or rate pain higher than those without anxiety.

To evaluate IANB success exclusively, no supplementary injections were given, and patients reporting moderate to severe pain were registered as failures. A limitation of our study was its limited sample size, based on the previous controlled clinical trial by Lahmann et al,¹⁹ who used a similarly small sample size to reduce dental anxiety via brief relaxation or music distraction. However, unlike the study by Lahmann et al,¹⁹ our study involved a more focused and specific clinical intervention which could enhance the reliability of the results despite the small sample size. Also, our a priori power analysis was performed to help ensure that the study was adequately powered to test our hypothesis. While larger samples always increase confidence in the results, we feel our findings are still valid within the context of our study’s controlled conditions and specific interventions.

In the future, multicentric clinical trials with larger sample sizes should be performed on all teeth with different pulpal diagnoses using different local anesthetic solutions and techniques. Future studies should also ensure a study protocol where each group is subjected to the same conditions. In addition, different forms of music (preferred or unpreferred) and/or music vs standard opioid approach should be compared to achieve definite clinical conclusions.

CONCLUSION

Within the limitations of this study, distraction with music was associated with higher local anesthetic success rates than the use of etizolam or placebo during endodontic treatment of mandibular molars with SIP.