Abstract
Background
Procedures in oral surgery, especially surgical extraction of the impacted mandibular third molar is often considered anxiety-producing and stressful. This study evaluated the effect of oral sedation (5 mg diazepam) on the physiological stress level in subjects that underwent surgical extraction of the mandibular third molar by measuring the change in salivary cortisol concentration.
Subjects and methods
204 salivary samples were collected from 102 subjects between 9.00 am and 12.00 pm to standardise the diurnal variations of cortisol secretion. Saliva samples were collected 45 min before and 15 min after surgical extraction from each subject in either group. The samples were stored in the freezer (− 20 °C) until analysis was done in the laboratory using salivary cortisol ELISA kits (DiaMetra S.r.l., Eagle Biosciences, Italy), and the cortisol concentration was measured with a microplate reader.
Results
There was a statistically significant change (p = <0.001 between the pre-surgical extraction salivary cortisol concentration of all subjects with a median of 7 ng/ml and post-surgical extraction salivary cortisol concentration of both the study and the control groups with a median of 17 ng/ml and 15 ng/ml, respectively. Only 11.8% of subjects in the study group had a reduction in post-surgical salivary cortisol concentration, while in the control group, 3.9% of subjects had a reduction in post-surgical salivary cortisol concentration. There was no statistically significant difference between the two groups (p = 0.135).
Conclusions
Hence, oral sedation has no significant impact on physiological stress during the surgical extraction of the mandibular third molar. However, salivary cortisol concentration can adequately reflect the stress induced by surgical extraction in subjects and its usefulness as a biomarker in stress research. Furthermore, the type of disimpaction of mandibular third molar affects salivary cortisol concentration, with distoangular disimpaction having the highest cortisol concentration and more stressful to subjects when compared to other types of disimpaction.
Keywords: Stress, Saliva, Cortisol, ELISA, Sedatives
Introduction
Procedures in oral surgery, especially surgical extraction of the mandibular third molar are often considered anxiety-producing, and the expectation of such an event is likely a valid cause of stress [1]. Patients may present with symptoms such as sweating, tremors, arrhythmias, and syncope, which could make treatment difficult or even impossible [2]. Stress is a psychological or physiological reaction by the defence mechanism of an organism against internal or external threats [3]. This mechanism consists of the autonomic nervous system (ANS) and the hypothalamic–pituitary–adrenocortical (HPA) axis [3]. The ANS mediates the secretion of catecholamines (epinephrine and norepinephrine) which are responsible for elevated heart and respiratory rates, increased blood flow to muscles, and high blood glucose [3]. The HPA axis is involved in the secretion of glucocorticoids (e.g. cortisol) [3]. Therefore, during a stressful situation, the body`s homeostatic response often leads to the release of corticotropin-releasing hormone, adrenocorticotropic hormone, and glucocorticoids (cortisol) [4]. In this regard, several authors have used this resultant release of cortisol into the body fluids such as saliva, as an evaluation of stress [5].
Pain and dentistry are often synonymous in the minds of patients [6]. Accumulating evidence now shows that these misinterpretations and the associated pain-related fear often cause a cascade of psychological and physical events including hypervigilance, muscular reactivity, avoidance and guarding behaviours, which in turn can perpetuate pain problems [7]. The injection of the local anaesthetic agent during dental extraction is often the only perceived painful part of the procedure, and fear associated with local anaesthetic injection has been reported to be a factor in avoiding dental treatment [8].
During invasive procedures like surgical extraction of the mandibular third molar, it is imperative to reduce the stress involved, and sedative measures have been used. Such measures include “minimal sedation” which is a drug-induced impairment of a patient’s cognitive function and coordination, while the cardiovascular systems and spontaneous breathing, as well as the verbal response, are unaffected [2]. Other sedative measures include hypnosis [9], brief relaxation, and audiovisual distraction [10]. There are several oral sedatives which include chloral hydrate, barbiturates (phenobarbital), and benzodiazepines (diazepam, midazolam). The benzodiazepines are the most widely used class of drugs for anxiolysis and sedation due to their efficacy and safety profile [11]. For the present study, diazepam was considered because it is the only sedative that is present in oral form in Nigeria.
This study evaluated the effect of oral sedation on the stress level in subjects that underwent surgical extraction of mandibular third molar by measuring the change in salivary cortisol concentration before and after surgical extraction.
Subjects and Methods
This research was a prospective randomized controlled study.
102 subjects, who visited the oral and maxillofacial surgery outpatient clinic (of Lagos State University Teaching Hospital) for surgical extraction of the impacted mandibular third molar and met the inclusion criteria were included in this study. The study duration was 6 months. Subjects aged between 21 and 65 years, were randomly allocated through balloting into the study group (51)—defined as subjects that took 5 mg diazepam per oral 45 min before surgical extraction, and control group (51)—defined as subjects that took no form of sedation before surgical extraction sedation. Each subject was asked to randomly pick among folded 102 pieces of papers in a box on which 51 pieces are tagged sedatives, while the remaining 51 pieces are tagged no sedatives. Whatever piece of paper that was selected by the subject was used for each case. The option of administering a placebo was considered, but several studies have shown that placebos can have similar effects as the test drug [12–14], for example, in the study by Jerjes et al. [14], placebos showed sedative effects in 3 patients on the day of surgery. Exclusion criteria included subjects that were allergic to the local anaesthetic agent, benzodiazepines, on routine contraceptives, using steroids, subjects with a debilitating medical condition, psychiatric patients, tobacco smokers, and alcohol abusers. Other exclusion criteria include pregnant subjects, those observing their menstruation, subjects with conditions of altered cortisol secretion (Addison’s disease, Cushing’s syndrome, and congenital adrenal hyperplasia), and altered secretion of saliva (caused by atropine, calcium channel blockers, antidepressants, antihistamines, Sjogren’s syndrome, and radiotherapy). Subjects that are overtly anxious about dental treatment using the modified dental anxiety scale and scoring > 19 [15] were also excluded from the study.
Before the collection of saliva, subjects were asked to avoid food and drink 1 h before saliva collection and also to rinse their mouth with plain water to clear away any debris or food particles. 1–2 mls of saliva was collected from subjects’ unstimulated glands (before administering oral diazepam in the study groups) using a salivette at 45 min before (onset of action of oral diazepam is about 40 min and to standardise saliva collection between the two groups), and 15 min after surgical extraction (some authors reported that peak salivary cortisol concentration is reached at ≥ 15 min after extraction [16, 17]). The surgical extraction was done between 9.00 am and 12.00 pm to standardise the diurnal variations of the secretion of cortisol. The two groups had surgical extraction of the mandibular third molar done under local anaesthesia by the same surgeon (a senior resident doctor) and a senior dental surgeon assistant using the same technique. The samples were labelled according to subjects group and unique ID number and stored in the freezer at − 20 °C until cortisol detection assay. Cortisol was detected in saliva using salivary cortisol ELISA (enzyme-linked immunosorbent assay) kits (DiaMetra S.r.l., Eagle Biosciences, Italy) and quantified with a microplate reader (Biocom, USA). All samples were removed from the freezer and allowed to thaw at room temperature followed by centrifugation at 3000 rpm for 15 min. While the calibrators were provided by the manufacturer, the diluted conjugate and the wash solution were prepared according to the manufacturer`s protocol. 25 µL of each saliva sample was withdrawn into a 96-well plate, placed in the microplate and incubated at 37 °C for 1 h. The contents of each well were removed and washed three times, using 300 µL of the diluted wash solution. One hundred mLs (100 mls) of TMB (tetramethylbenzidine) substrate was added to each sample and incubated in the dark at room temperature for 1 min, and this produced a bluish colouration. This was followed by the addition of 100 µL stop solution, which changed the colour to yellow. The colour intensity was inversely proportional to the cortisol concentration in the samples. The absorbance was read at 450 nm using a microplate reader/photometer. A calibration curve was derived by plotting the absorbance values of the calibrators against cortisol concentration. The values of the samples were interpolated from the calibration curve to get the corresponding values of the cortisol concentration expressed in ng/mL.
Statistical analysis was done using the Statistical Package for Social Sciences (IBM) 23.0 version. The significant level was set at a p value of < 0.05 at 95% confidence interval.
Results
204 salivary samples from 102 subjects were assayed. There was a change in the pre-surgical (median = 7 ng/ml) and post-surgical extraction salivary cortisol concentrations of subjects in both groups (study group median = 17 ng/ml and control group median = 15 ng/ml) (p = <0.001) (see Table 1). The post-surgical extraction salivary cortisol concentrations in both groups were not significantly different (p = 0.558) (see Table 2). However, 6/51 (11.8%) subjects in the study group had a reduction in post-surgical salivary cortisol concentration in comparison with 2/51 (3.9%) subjects in the control group who also had a reduction in post-surgical salivary cortisol concentration (p = 0.135) (see Fig. 1). The mean operating time in this study was 30.9 ± 6.6 min and 29.0 ± 9.9 min in the study and the control groups, respectively, with no statistically significant difference between the two groups (p = 0.223). Median comparison of the change in salivary cortisol concentration according to the type of disimpaction, with distoangular disimpaction having the highest, 19 ng/ml (see Table 3).
Table 1.
Median comparison between the pre-surgical extraction salivary cortisol and post-surgical extraction salivary cortisol concentrations in the two groups
| Pre-extraction (ng/ml) | Post-extraction (ng/ml) | W value | p value | |
|---|---|---|---|---|
| Study group | ||||
| Median (Q1, Q3) | 7.0 (4.0, 9.8) | 17.0 (10.0, 28.0) | − 5.897 | < 0.001* |
| Range | 2.0, 20.5 | 5.0, 99.0 | ||
| Control group | ||||
| Median (Q1, Q3) | 7.0 (4.2, 9.5) | 15.0 (10.5, 27.3) | − 6.163 | < 0.001* |
| Range | 3.5, 18.0 | 7.2, 59.0 | ||
There was a statistically significant difference between the pre- and post-surgical extraction salivary cortisol levels in both groups (p = < 0.001)
W = Wilcoxon sum rank test; Q1, Q3—First quartile and third quartile, respectively
*Significant
Table 2.
Median comparison of post-surgical salivary cortisol concentrations in the two groups
| Study group (ng/ml) | Control group (ng/ml) | U value | p value | |
|---|---|---|---|---|
| Salivary cortisol | ||||
| Median | 17.00 | 15.0 | − 0.586 | 0.558 |
| Q1, Q3 | 10.1, 28.0 | 10.5, 27.1 | ||
| Range | 5.0, 99.0 | 7.2, 59.0 | ||
There was no statistically significant difference between the salivary cortisol concentrations in the two groups (p = 0.558)
U = Mann–Whitney U test; Q1, Q3—First quartile and third quartile range, respectively
Fig. 1.
Multiple bar chart showing a change in cortisol concentration in the two groups. X2 = 2.170, p = 0.135
Table 3.
Median comparison of the change in salivary cortisol concentration according to the type of disimpaction, with distoangular disimpaction having the highest, 19 ng/ml
| Median (Q1, Q3) (ng/ml) | K | p value | |
|---|---|---|---|
| Type of disimpaction | |||
| Mesioangular | 6.50 (3.2, 13.0) | 8.293 | 0.040* |
| Vertical | 16.25 (11.5, 29.8) | ||
| Horizontal | 8.30 (6.2, 12.0) | ||
| Distoangular | 19.0 (18.3, 21.4) | ||
K—Kruskal Wallis test; Q1, Q3—First quartile and third quartile range, respectively
Figure 1 shows the change in salivary cortisol concentrations in the study and control groups, where change = the difference between baseline salivary cortisol concentration and post-surgical extraction salivary cortisol concentration. In the study group, 45 (88.2%) out of the 51 subjects had an increase in cortisol concentration, while the remaining 6 (11.8%) subjects had a reduction in salivary cortisol concentration. In the control group, 49 (96.1%) out of 51 subjects had an increase in salivary cortisol concentration, while the remaining 2 (3.9%) subjects had a reduction in salivary cortisol concentration. There was no statistically significant difference between the two groups, p = 0.135.
Figures 2 and 3 show a positive Spearman correlation (r) between change in salivary cortisol level and duration of surgery, with values of r = 0.329 and 0.227 in study and control groups, respectively. It was observed that as the duration of surgery increased the salivary cortisol level also increased. This relationship was statistically significant (p = 0.018 and 0.039 for study and control groups, respectively).
Fig. 2.
Positive correlation between change in salivary cortisol concentration and duration of surgery in the study group. Spearman correlation (r) = 0.329, p = 0.018*
Fig. 3.
Positive correlation between change in salivary cortisol concentration and duration of surgery in the control group. Spearman correlation (r) = 0.227, p < 0.039*
Discussion
Researchers world over have used sedatives to alleviate stress in dental extraction, and the measure of the effectiveness of these sedatives is through stress markers quantitation [14, 16, 17]. To ascertain this fact, salivary cortisol as a measure of stress was considered in this study following sedation during surgical extraction of the mandibular third molar. In this study, it was demonstrated that there was an increase between the pre-surgical extraction and the post-surgical extraction salivary cortisol concentrations of all subjects (p = <0.001). This increase in salivary cortisol concentration was adjudged to be the result of the subjects’ response to stress induced by surgical extraction. This was in agreement with the findings of Miller et al. [16], Gadicherla et al. [18], and Umeanuka et al. [5] who showed an increase in salivary cortisol level after completion of tooth extraction.
A basic confounder in stress-induced salivary cortisol concentration quantitation is the detection at peak salivary cortisol concentration. Some authors reported that peak salivary cortisol concentration is reached at ≥ 15 min after extraction [16, 17, 19]. In support of the literature, saliva samples for cortisol measurement were taken at 15 min post-surgical extraction, and it was observed that there was a rise in salivary cortisol concentration.
Sedatives are believed to blunt the increase in cortisol in the postoperative period of extraction through their anxiolytic and amnesic properties [20] by preferentially acting on midbrain ascending reticular formation (which maintains wakefulness) and on the limbic system (thought and mental functions) [21]. However, this premise was not supported in this study, as only 6/51 (11.8%) subjects in the study group had a reduction in post-surgical salivary cortisol concentration besides 2/51 (3.9%) control participants had a reduction in post-surgical salivary cortisol concentrations (there was no statistically significant difference between the two groups, p = 0.135). Perhaps, the 5 mg diazepam per oral used had little or no effect on the salivary cortisol levels of the subjects. This is in agreement with a related study by Shanmugaavel et al. [22], where they found no significant reduction in salivary cortisol level following the use of intranasal and sublingual midazolam despite a reduction in anxiety level of the subjects. In addition, there is the possibility of individual variability in response to a specific dose of benzodiazepine [14]. Although, midazolam was reported to be the sedative of choice for reducing stress-induced salivary cortisol [14, 23]. In the current study, diazepam was used (as it is the only sedative available in oral form in Nigeria) which slightly differs pharmacologically from midazolam.
It was observed in this study that there was a positive correlation between change in salivary cortisol concentration and duration of surgery in the two groups. As the duration of surgery increased the salivary cortisol concentration also increased, this relationship was statistically significant with p = 0.018 and 0.039 in the study and the control groups, respectively. This means that the longer the duration of surgery, the higher the cortisol concentration and the more stressful the procedure was likely to become. This is consistent with the studies by Jerjes et al. [14] and Steer et al. [20], where they found that the duration of surgery was associated with elevated salivary cortisol concentration. Generally, the duration of surgery is considered as the gold standard for measurement of intra-operative difficulty in mandibular third molar surgery [24]. Yuasa et al. [25], reported a mean operating time of 30 min in their study. This is in agreement with the mean operating time in this study, which was 30.9 ± 6.6 min and 29.0 ± 9.9 min in the study and the control groups, respectively; however, there was no statistically significant difference between the two groups (p = 0.223). Although some studies have documented a lesser mean operating time [26–28]. Factors such as the angulation and depth of impaction, the experience of the surgeon, type of anaesthetic technique, patient’s cooperation, speed and sharpness of bone-cutting instruments have been reported to contribute to the variations in the operating times [29, 30]. Furthermore, it was observed that the median change in post-surgical salivary cortisol concentrations varied with the type of disimpaction. Mesioangular disimpaction had the least change in post-surgical salivary cortisol concentration (6.5 ng/ml) followed by horizontal disimpaction (8.3 ng/ml) and vertical disimpaction (16.3 ng/ml). However, distoangular disimpaction had the highest salivary cortisol concentration (19 ng/ml). This probably is a reflection of the level of stress associated with each type of disimpaction, with mesioangular disimpaction being the least stressful and distoangular disimpaction the most stressful.
Conclusion
This study interrogated the effect of sedation on physiological stress during mandibular third molar surgery and demonstrated that oral sedation of 5 mg diazepam had no significant effect on salivary cortisol concentration. However, this study was able to show a significant rise in salivary cortisol concentration following surgical extraction of the impacted mandibular third molars in both groups of subjects. Furthermore, the type of disimpaction of mandibular third molar affects salivary cortisol concentration, with distoangular disimpaction having the highest cortisol concentration and by implication more stressful to subjects when compared to other types of disimpaction. Also, the longer the duration of a surgical procedure, the more stressful the procedure, which will reflect as a rise in salivary cortisol concentration. Finally, the assessment of salivary cortisol offers the opportunity to collect samples stress-free compared to other body fluids.
Limitation of the Study
The effect of sedation on stress probably would have been demonstrated if multiple saliva samples were taken at the different stages of the procedure (after giving local anaesthetic agent, intraoperative, and immediate postoperative), but this was difficult due to blood-stained saliva. Also, the effect of sedation on stress would have been more objective if subjects were made control of themselves (subjects with bilateral impacted mandibular third molar).
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Ethical Aapproval
All procedures performed in this study involving human participants were in accordance with the ethical standards of the Health Research and Ethics Committee of the Lagos State University Teaching Hospital.
Consent to Participate
Informed consent was obtained from all individual participants included in the study.
Consent for Publication
Informed consent was obtained from all individual participants for publication.
Availability of Data and Material
Documentation of data and material for the study are included.
Footnotes
Publisher's Note
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