Melatonin and Alprazolam as Anxiolytic Agents in Minor Oral Surgical Procedures – A Comparative Study

Abstract

Introduction:

Dental anxiety has a major impact on patient compliance, which frequently requires pre-operative pharmacological intervention. Although commonly utilised, melatonin, an endogenous hormone with analgesic and anxiolytic effects and alprazolam, a short-acting benzodiazepine, are not frequently compared in minor oral surgical procedures. This study compares melatonin and alprazolam as anxiolytic and analgesic agents in patients undergoing minor oral surgical procedures.

Materials and Methods:

In a triple-blind, randomised controlled trial, 42 American Society of Anesthesiologists (ASA) I/II patients (ages 20–50) with pre-operative anxiety (visual analogue scale [VAS] >50) were randomly assigned to either oral melatonin 3 mg (Group A) or oral alprazolam 0.5 mg (Group B) one hour prior to surgery. Pre-, intra- and postoperatively, anxiety (VAS, Trail Making Test), sedation (Ramsay Sedation Scale) and recovery (Modified Aldrete Score) were evaluated. The Mann–Whitney U and Wilcoxon signed-rank tests (SPSS v25) were used for statistical analysis.

Results:

Both groups showed a significant intra-group decrease in VAS anxiety scores (P < 0.001). A post-operative inter-group comparison showed that melatonin provided superior anxiolysis (P = 0.03) and less sedation (P = 0.01). The modified Aldrete scores were similar (P = 1.00), and no negative effects were noted.

Discussion:

Although both treatments are successful in lowering perioperative anxiety, melatonin’s superior anxiolytic effects and a positive sedation-recovery profile make it a potential substitute for benzodiazepines in minor oral surgical operations.

INTRODUCTION

The term anxiety is a sense of unease or anxiety brought on by a perceived or actual threat. It is essential to distinguish between dental anxiety and dental phobia. Dental anxiety is a common state of apprehension before or during procedures, usually manageable with behavioural or pharmacological measures. Dental phobia, however, is a severe and persistent fear leading to avoidance of care and often requires specialised interventions. This study addressed dental anxiety only and excluded cases of dental phobia. From previous literature, it has been found that nearly 20% of patients avoid going to the dentist as they are anxious about unpleasant dental experiences they came across in the past.[1] This can result in treatment problems and deteriorating oral health. Patients with dental anxiety are more likely to be female, especially if they are middle-aged or older. Dental anxiety is a significant obstacle to undergoing dental treatment.[2] One of the most frequent causes of anxiety in dental practice is minor oral surgical procedures.[3] Clinically, symptoms of anxiety include elevated blood pressure, pulse rate, salivation and restlessness, which can be detected early. Untreated pre-operative anxiety might impair anaesthesia effectiveness, lower pain threshold and exacerbate intraoperative difficulties.[4]

For successful results, dental anxiety must be effectively managed. Oral pre-medication is a commonly accepted pharmacological approach.[5] Melatonin and alprazolam are two frequently used oral medications that have anxiolytic and analgesic effects. Melatonin is a hormone produced by the pineal gland, that controls the sleep-wake cycle and has anti-inflammatory, anxiolytic, analgesic and antioxidant properties. It is inherently inhibited by light and secreted in reaction to darkness. Melatonin is frequently used to treat ailments like jet lag, sleeplessness and irregular circadian rhythms because it operates on MT1 and MT2 receptors. Melatonin has a half-life of 35–50 min and reaches peak plasma levels when given orally in about an hour. With only minor adverse effects, including headache and sleepiness, it is usually well-tolerated.[6,7,8]

Alprazolam is a common benzodiazepine used to treat anxiety and panic disorders. It promotes drowsiness and anxiolysis by amplifying the effects of gamma-aminobutyric acid (GABA) at the GABA-A receptor. Peak levels of alprazolam are obtained in 1–2 h due to its rapid absorption. The liver (CYP3A4) breaks it down and excretes it in urine. Alprazolam is an effective medication, but prolonged usage entails a risk of dependency.[9,10,11] With this background, this study aims to compare the anxiolytic and analgesic effects of melatonin (3 mg) and alprazolam (0.5 mg) in patients undergoing minor oral surgical procedures, to assess their effectiveness and safety in managing dental anxiety.

MATERIALS AND METHODS

A triple-blind, controlled clinical study was conducted in the Department of Oral and Maxillofacial Surgery. The study population comprised 42 patients, aged 20–50 years, classified as American Society of Anesthesiologists (ASA) I or II, and exhibiting a pre-operative anxiety score >50 on the visual analogue scale (VAS). On the 0–100 VAS, scores between 0 and 50 generally indicate mild-to-moderate anxiety, while scores above 50 reflect clinically significant or high anxiety. In this study, a cut-off of >50 was used to categorise patients as experiencing marked anxiety. This threshold aligns with prior use of the VAS in assessing pre-operative dental anxiety, where the midline (50) serves as the transition point between acceptable and high anxiety levels. Participants were excluded if they were pregnant, on anxiolytic medications or had a history of substance abuse. The required sample size (n = 42; 21 per group) was determined using G*Power 3.1.9.7 software (effect size: 0.8, α =0.05, power = 80%).

Following approval from the Institutional Ethical Committee (Protocol No: Pr. 184/IEC/SIBAR/2023) and informed written consent, patients were randomly allocated into two groups using a lottery method. Group 1 received 3 mg melatonin [Figure 1] and Group 2 received 0.5 mg alprazolam [Figure 2], administered orally one hour prior to surgery. All participants were isolated post-medication to minimise external stimuli. Baseline parameters, including VAS for anxiety and Trail Making Test (TMT), were recorded. Intraoperative sedation was assessed using the Ramsay Sedation Scale, and post-operative evaluations included VAS, TMT-B, and the modified Aldrete Score. Data were compiled by using Microsoft Excel software and analysed by using Statistical Package for the Social Sciences (SPSS) version 26 IBM Corp, Armonk, Newyork, USA.

Figure 1.

Bar graph depicting the mean age of study participants

Figure 2.

Pie diagram depicting the distribution of study participants according to gender

RESULTS

Figure 1 illustrates the mean age of all participants as 32.1 ± 3.9 years, with the mean for Group A being 32.4 ± 3.8 years and the mean for Group B being 31.8 ± 4.1 years. The overall gender distribution of participants was 52.4% females and 47.6% males [Figure 2]. Table 1 analyses the pre-operative VAS anxiety scores using the Mann–Whitney U Test and finds no statistically significant difference between the groups. Table 2 illustrates the post-operative VAS anxiety scores, revealing a statistically significant difference (P = 0.03) between the groups. The intraoperative Ramsay sedation scores are compared between the groups in Table 3, which shows a statistically significant difference (P = 0.01) between the two groups as determined by the Mann–Whitney U test. There is no statistically significant difference between the groups’ post-operative modified Alderete scores as determined by the Mann–Whitney U-Test [Table 4]. The intra-group comparison of VAS anxiety scores before and after surgery is evaluated in Table 5, which shows a statistically significant decrease in anxiety levels within Group A (P = 0.00) and Group B (P = 0.00), according to the Wilcoxon signed-rank Test.

Table 1.

Inter Group comparison of Visual Analogue Scale for Anxiety scores pre-operatively between both the groups using Mann-Whitney U Test

Group	Mean Rank	Z	P	Effect size (r)	95% CI
Melatonin	21.00	0.00	1.00	0.00	[–0.30, 0.30]
Alprazolam	21.00

Cl: Confidence interval

Table 2.

Inter Group comparison of Visual Analogue Scale for anxiety scores post-operatively between both the groups using Mann-Whitney U Test

Group	Mean Rank	Z	P	Effect size (r)	95% CI
Melatonin	17.36	–2.14	0.03*	0.33	[0.05, 0.56]
Alprazolam	24.83

*Illustrates the postoperative VAS anxiety scores, revealing a statistically significant difference (P=0.03) between the groups. Z: Mann–Whitney U test statistic, P: Probability value, r: Effect size, CI: Confidence interval

Table 3.

Inter Group comparison of Intra-operative Ramsay sedation scores using Mann-Whitney U Test

Group	Mean Rank	Z	P	Effect size (r)	95% CI
Melatonin	23.50	–2.41	0.01*	0.37	[0.09, 0.59]
Alprazolam	18.38

*Illustrates the intraoperative Ramsay Sedation scores are compared between the groups, which shows a statistically significant difference (P=0.01) between the two groups. Z: Mann–Whitney U test statistic, P: Probability value, r: Effect size, CI: Confidence interval

Table 4.

Inter Group comparison of Modified Alderete score post-operatively using Mann-Whitney U Test

Group	Mean Rank	Z	P	Effect size (r)	95% CI
Group A	21.00	0.00	1.00	0.00	[–0.30, 0.30]
Group B	21.00

Cl: Confidence interval

Table 5.

Intra Group comparison of Visual Analogue Scale for Anxiety scores pre and post-operatively among both the groups using Wilcoxon Signed Rank Test

Group	Time Interval	Mean Rank	Z	P	Effect size (r)	95% CI
Group A	Pre-op	11.00	–4.13	0.00*	0.90	[0.64, 0.98]
Group A	Post-op	0.00
Group B	Pre-op	10.50	–3.95	0.00*	0.86	[0.58, 0.96]
Group B	Post-op	0.00

CI: Confidence interval

DISCUSSION

The anxiolytic effectiveness of melatonin and alprazolam was assessed in this trial in individuals undergoing minor oral surgical procedures such as basic extractions, transalveolar extractions, disimpactions and alveoloplasty. There were 42 participants in all, both men and women, with ages ranging from 20 to 50. In many cases, dental fear and anxiety, which are widespread problems worldwide, result in treatment avoidance, decreased cooperation and worse results. It is necessary to control these psychological variables to provide good dental treatment. Anxiety still affects psychological and physiological responses, leading to missed appointments and treatment difficulties, even with advancements in dental technology. As a result of patient demand and enhanced safety profiles, sedative pre-medication has gained popularity.

Nonetheless, with substances like melatonin and alprazolam undergoing extensive research, pharmacological treatments remain the most dependable. Using reliable methods like the Ramsay sedation scores and the VAS, which have been used for decades, this systematic review assessed anxiety and sedation levels.[10]

The pineal gland’s main hormone is melatonin, which is released at night. The nighttime melatonin peak regulates the physiological processes in the dark. As an interface between the light-dark cycle, the pineal gland has neuroendocrine functions.[11] In 1959, Lerner initially isolated it from the pineal gland of cattle. It is primarily metabolised by the liver and eliminated as 6-hydroxy-melatonin sulphate, with a short biological half-life.[12] Three subtypes – MT1, MT2 and MT3 – exist for melatonin cell membrane receptors in other mammals and humans. Most of melatonin’s biological effects are mediated by the G-protein-coupled MT1 and MT2 receptors, which display high amino acid homology and complementarily control the circadian rhythm and immune system in the central nervous system.[12]

The retinohypothalamic tract regulates its primary secretion at night, which is regulated by circadian rhythms produced in the suprachiasmatic nuclei[10] and synchronised with the light-dark cycle. Melatonin has receptor-dependent and independent effects, modulating redox balance, inflammation and fibrosis pathways by acting through autocrine and paracrine mechanisms.[11] Its main physiological role is the synchronisation of biological rhythms, and even low doses maintain this function. Melatonin’s sedative, anxiolytic and possible analgesic effects make it a potential pre-surgical medication because it reduces both pre-operative excitement and required anaesthetic doses.[6] Melatonin receptors MT1 and MT2 regulate GABA activity, resulting in anxiolysis and sedation.[13] Melatonin has been utilised as pre-medication prior to general anaesthesia because studies have demonstrated that it raises central GABA levels in a dose-dependent manner.[14]

Some of melatonin’s analgesic mechanisms include interactions with the nitric oxide route, opioid receptors, β-endorphins and GABA receptors. The opioid pathways are implicated by the fact that naloxone reverses melatonin’s analgesic effect. Melatonin also inhibits the recruitment of polymorphonuclear cells, reduces cyclooxygenase activity and downregulates inflammatory mediators like NO and NF-κB. Its effect follows a circadian rhythm: animal studies have shown that pain sensitivity is reduced during the time of maximum melatonin release and that the rhythm is disrupted after pinealectomy.[15,16]

Circadian rhythms are frequently disrupted by surgical stress. Oral melatonin improves sleep, circadian stability and pre-operative calmness. In addition, MT1/MT2 receptor agonists like agomelatine have anxiolytic effects in animal models.[17] Adult trials (such as 5 mg pre-operatively) demonstrated a notable reduction in anxiety and an improvement in post-operative recovery.[18] The results in youngsters are mixed: While other research revealed midazolam to be superior,[19] Samarkandi et al., discovered that melatonin (0.25–0.5 mg/kg) was equivalent to midazolam.[20] According to de Carvalho Nogueira et al., people benefited from the use of melatonin, which helped them sleep well at bedtime before surgery and minimising opioid use during the procedure.[21] Seet et al., reported gender-specific reactions, with notable effects in women.[22] The literature shows dose-dependent action of melatonin ranging from 3 mg daily to 6 mg single doses.[23] Up to 0.4 mg/kg of melatonin was given by Kain et al., and no negative side effects were seen.[24]

All these study results strongly supporting the present study findings, as there is a significant decrease in the anxiety levels of patients when compared to pre- and post-surgical procedures as the mean rank values strongly suggesting the effective use of melatonin as an anxiolytic agent; the mean rank values of pre- and post-surgical procedures are 11.00 and 0.00, respectively, which is statistically significant.

Due to their anxiolytic, amnesic and sedative properties, benzodiazepines continue to be a well-liked pre-operative medication. Alprazolam, a triazolobenzodiazepine, is more anxiolytic-selective than midazolam or diazepam. It is metabolised by CYP3A enzymes and contraindicated with agents like ketoconazole and itraconazole.[9] It enhances inhibitory neurotransmission by binding to GABA-A receptors, reducing excessive anxiety and restlessness. Despite the need for caution due to the possibility of dependence and withdrawal symptoms, it is frequently used to treat generalised anxiety disorder, panic disorder and related conditions.[25] In the 1980s and 1990s, alprazolam (0.5–3.0 mg/day) was assessed in several trials for the treatment of GAD (generalised anxiety disorder), frequently using the Hamilton Anxiety Scale.[26] Alprazolam consistently demonstrated a marked improvement over placebo, with a quick onset. A 6-week double-blind trial discovered that alprazolam (1.9 mg/day) was as effective as buspirone (18.7 mg/day) but with quicker symptom relief.[27] The systematic review conducted by Boettler et al., suggests that the short-term use of oral benzodiazepines, such as alprazolam, for periprocedural anxiolysis is both safe and effective.[28]

In addition to anxiety, alprazolam has been shown to be helpful in treating chemotherapy patients who suffer from anticipatory nausea, panic-related atypical chest discomfort and chronic pain.[29] Rickels et al., discovered that alprazolam and diazepam both had comparable improvements, both of which were better than placebo.[30] According to Chouinard et al., alprazolam was much more effective than placebo in treating anxiety and panic disorders.[27] Supporting earlier results, this research found that alprazolam (0.5 mg) caused a significant decrease in anxiety (mean rank scores pre- and post-procedure: 10.50 and 0.00). It is noteworthy that trial-making cognitive tests revealed no impairment, proving that these low dosages are safe to use.

While both medications reduced anxiety scores noticeably, melatonin had more impact. Benzodiazepines like alprazolam cause deeper sedation, whereas melatonin causes lighter sedation with sufficient anxiolysis, which lessens the need for intensive monitoring. A Belgian study found that oral alprazolam (0.5 mg) had a greater sedative effect than placebo,[30] and the same results were seen in this study. Oral melatonin (5 mg) also produced significant sedation in 60–90 min.[31] Interestingly, prior research has shown that combination therapy improves anxiolysis without increasing sedation.[32] Pokharel et al., compared the pre-medication benefits of alprazolam plus melatonin to those of each medication taken alone. When melatonin was added to alprazolam, the anxiolytic effects were better than those of either drug alone or placebo. When combined with alprazolam, melatonin did not increase the amnesic effect or worsen the sedation score.[33]

Melatonin exhibited a calmer profile when comparing sedation levels, while alprazolam caused greater sedation. This is consistent with Naguib and Samarkandi’s findings that both drugs induce more sedation than a placebo.[34] Mean rank comparisons in this study (melatonin 17.86 vs alprazolam 24.83) revealed that melatonin achieved superior anxiety reduction. According to Khare et al., melatonin (6 mg) is a good alternative to alprazolam, with improved anxiolysis and maintained psychomotor function.[35] Additional trial has shown melatonin’s perioperative advantages, such as decreased delirium.[36] Other trials have demonstrated melatonin’s effects on anxiety reduction, pain modulation, antioxidant activity and enhanced neurosensory recovery.[37,38,39] The effectiveness and safety of oral melatonin versus oral alprazolam as premedication for adult patients having a range of elective surgical procedures under general anaesthesia were compared by Kanthed et al. The study suggests that oral melatonin (3 mg) is a more effective and safer alternative to alprazolam (0.5 mg), as it has the potential to reduce pre-operative anxiety by providing less sedative side effects and hemodynamic stability.[40]

This study has certain limitations that warrant consideration. Although the sample size (n = 42) was statistically calculated, it remains relatively small, which may restrict the generalisability of the findings. Randomisation was performed using the lottery method; while simple and feasible in the clinical setting, this approach may not eliminate allocation bias compared to computerised randomisation techniques. Furthermore, the study focused exclusively on immediate perioperative outcomes, without long-term follow-up, which limits the ability to assess the sustained anxiolytic efficacy or potential delayed effects of melatonin and alprazolam.

CONCLUSION

The results of the present study yield important information regarding the comparative efficacy of melatonin and alprazolam as anxiolytics for patients experiencing minor oral surgery. Melatonin and alprazolam showed a very pronounced decrease in anxiety, and the patients noted that they experienced less fearfulness and a calmer state throughout the surgical intervention. In general, the research indicates that melatonin holds great potential as a substitute for alprazolam in treating anxiety during minor oral surgical procedures, especially for patients who are worried about the dangers of benzodiazepines. Yet more extensive studies with greater sample sizes and more diverse patient populations are necessary to confirm these results and to investigate long-term outcomes, including the possibility of melatonin’s wider use across other medical and dental contexts. In conclusion, while both melatonin and alprazolam have their merits as anxiolytic agents, melatonin stands out as a preferable option for patients seeking a safer, more natural solution for managing anxiety, especially in the context of minor oral surgeries where long-term use of medications like alprazolam is not ideal.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.