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A STUDY OF MELATONIN FOR PREMEDICATION PRIOR TO ANESTHESIA
By
Daniel Lee
A thesis submitted in conformity with the requirements
for the degree of Master of Science
Graduate Department of Dentistry
University of Toronto
© Copyright by Daniel Lee, 2009
II
Daniel Lee
A STUDY OF MELATONIN FOR PREMEDICATION PRIOR TO ANESTHESIA
Master of Science, 2009
Graduate Department of Dentistry
University of Toronto
Abstract
Background: Anxiety is a barrier to dental care for many people. Preliminary studies
suggest that melatonin may possess anxiolytic and sedative properties. Methods: Twelve
subjects were selected for this study which compared melatonin, at a dose of 0.14 mg/kg,
with placebo, as an oral premedication for anxious dental patients prior to receiving a
general anesthetic. A visual analog scale (VAS) was used to measure anxiety. The
Richmond Agitation Sedation Scale (RASS) was used to assess sedation, the Trieger Dot
Test (TDT) for psychomotor impairment, and Digit Symbol Substitution Test (DSST) for
cognitive impairment. A Quality of Recovery Questionnaire (QoR) was completed 24
hours after each appointment. Results: There were no significant differences in VAS
scores for melatonin and placebo between baseline and at 30, 60, and 90 minutes. Similar
results were found for RASS scores, TDT, DSST, and the QoR. Conclusion: At the
doses used in this study, melatonin was not significantly different from placebo in
anxiolysis, sedation, cognitive impairment, psychomotor impairment, and quality of
recovery from anesthesia, for anxious dental patients.
III
Table of Contents
Section Page
Introduction
Oral Sedation in Dentistry
Pharmacology of Melatonin
Measuring Anxiety
Literature Review of Melatonin for Premedication
Assessments Used In The Study
Statement of Purpose
Methods
Data Analysis
Results
Discussion
Conclusion
Future Directions
References
Appendix
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4
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10
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14
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31
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IV
List of Tables
Table Name Page
1
2
3
4
5
6
7
8
9
10
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12
13
14
15
16
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Subject Information
Outcome Results For Melatonin Trial
VAS Score Results For Melatonin and Placebo Trials
VAS Results – Statistical Analysis For Melatonin Trial
VAS Results – Statistical Analysis For Placebo Trial
VAS Results – Statistical Analysis Comparing Melatonin
To Placebo
Within-Subject VAS Analysis
Heart Rate Results
Blood Pressure Results
Oxygen Saturation (SpO2) Results
Heart Rate – Statistical Analysis For Melatonin
Heart Rate – Statistical Analysis For Placebo
Heart Rate – Statistical Analysis Comparing Melatonin
To Placebo
Systolic Blood Pressure – Statistical Analysis For
Melatonin
Systolic Blood Pressure – Statistical Analysis For
Placebo
Systolic Blood Pressure – Statistical Analysis Comparing
Melatonin To Placebo
SpO2 Results – Statistical Analysis Comparing Melatonin
To Placebo
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57
60
V
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Richmond Agitation Sedation Scale Results
RASS Results – Statistical Analysis
Digit Symbol Substitution Test Results
DSST Results – Statistical Analysis
Trieger Dot Test Results
TDT Results – Statistical Analysis
Quality of Recovery Questionnaire Results
Quality of Recovery Questionnaire Results – Statistical
Analysis
Wilcoxon Signed Rank Test Results
DSST and TDT Score Comparison Between First and
Second Trials
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VI
List of Figures
Figure Name Page
1
2
3
4
5
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7
8
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VAS Evaluation Form
Richmond Agitation Sedation Scale
Trieger Dot Test
Digit Symbol Substitution Test
Quality of Recovery Questionnaire
VAS Score For Melatonin And Placebo Trials
VAS Difference Relative To Baseline
Within-Patient Difference For VAS
Average Heart Rate Differences
Average Systolic Blood Pressure Differences
Average Oxygen Saturation (SpO2)
RASS Score Results
Digit Symbol Substitution Test (DSST) Results
Trieger Dot Test (TDT) Results
Quality of Recovery Questionnaire (QoR) Results
Average DSST Scores For First and Second Trials
Average TDT Results For First and Second Trials
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VII
List of Appendices
Appendix Name Page
1
2
3
Inclusion and Exclusion Criteria Checklist
Consent Form
Information Sheet
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1
Introduction
Despite significant improvements to pain control in dentistry, fear and anxiety are
still major obstacles that prevent many people from receiving proper dental care
(Armfield et al., 2007). This can range from anxiety toward receiving a needle to severe
phobias toward everything that is dental. There are numerous sources of anxiety in the
dental clinic for these people: sound of hand pieces and drills, a particular odour of a
dental material, sight of needles and burs, or the feel of instruments in their mouths. The
issue of dental fear/anxiety/phobia is all the more important in the light of evidence that
dental health may be linked to general health (Guynup, 2006; Douglass et al., 2006;
Merchant, 2006). Dental anxiety is a serious concern in today’s society. By avoiding
dental care, the patient’s general health may also be affected, which negatively affects
their quality of life.
It has been estimated that 50 to 70% of people experience anxiety when visiting a
dentist, and 15 to 20% of people avoid the dentist due to fear (Economou, 2003). In the
United States alone it is believed that 45,000,000 people suffer from dental fear and
anxiety (Economou, 2003). Whether it is due to personal experience or anxiety induced
by what they have heard from others, these fearful experiences have long-term
implications because dental fear tends to be stable and difficult to eliminate (Armfield et
al., 2007). Fearful patients may delay or avoid dental treatment altogether. As increasing
amounts of scientific evidence show that oral health is important for general health, the
avoidance of dental care by a large subset of the population may result in significant
health issues in these individuals. Even if the treatment is provided under general
2
anesthesia for highly anxious patients, fear of needles can hamper the placement of an
intravenous line or there may be fear of being under anesthesia in addition to fear of the
dental procedure. One effective method of helping to reduce this sense of fear and
anxiety has been to provide an oral medication that acts as an anxiolytic.
The most commonly used oral anxiolytic medication for patients in dentistry has
been a drug from the benzodiazepine class, such as triazolam, midazolam, lorazepam, and
diazepam (Fragen et al., 1976; Lu et al., 2006). Benzodiazepines have a number of useful
properties that makes it an excellent premedicant: anxiolysis, sedation, amnesia, and
muscle relaxation. All of these factors make it easier for patients to endure the dental
procedures that they otherwise would not have been able to. These drugs can also be
administered orally, making them easy and convenient to use. By using such an oral
premedication, patients’ anxiety can be reduced to a level that makes it possible for them
to receive dental treatment or to be induced for general anesthesia. The use of such
premedications allows patients who would otherwise neglect their oral health to receive
needed care.
However, while benzodiazepines are good in providing anxiolysis, they have a
number of undesirable side effects (Lu et al., 2006). These drugs can delay recovery from
anesthesia. Diazepam and lorazepam have long half-lives, which could undesirably
prolong the time of sedation. Cognitive and psychomotor impairment may also be
prolonged. They should be avoided in patients with conditions such as narrow angle
glaucoma or myasthenia gravis, and is also relatively contraindicated in pregnant
3
patients. Benzodiazepines can cause paradoxical reactions such as excitation,
hallucination, or delirium. A number of these drugs also interact with certain
medications, such as erythromycin, cimetidine, and ritonavir that are biotransformed by
the same liver enzyme system (Lu et al., 2006). Furthermore, while this drug has a large
therapeutic index, it is still quite possible to overdose a patient on benzodiazepines that
could result in apnea and potential respiratory or cardiac arrest. Benzodiazepines also
have the potential for abuse and dependency.
Therefore, it would be advantageous to discover a substance that could be used
for premedicating anxious patients that is similar in anxiolytic effectiveness as
benzodiazepines but with less side effects and adverse reactions. Such a substance could
be melatonin. Various studies have shown that melatonin has the potential to be as good
in anxiolysis as benzodiazepines but without most of their side effects (Naguib et al.,
1999; Acil et al., 2004). Premedication with 0.05 mg/kg or 5 mg of melatonin
sublingually was shown to be associated with preoperative anxiolysis in adults without
psychomotor impairment or impact on recovery (Naguib et al., 1999; Acil et al., 2004).
Melatonin has no abuse potential, and is difficult to overdose on. Since melatonin is a
naturally occurring hormone in the human body, it may also more acceptable to patients
who may be uncomfortable in taking synthetic medications. Preoperative melatonin
administration was associated with faster recovery and lower incidence of postoperative
excitement than midazolam. Furthermore, melatonin does not appear to produce a
“hangover” effect like the benzodiazepines and other traditional sedatives (Acil et al.,
2004). Melatonin has a relatively short half-life, so prolonged sedation is less likely than
4
with benzodiazepines. If these findings could be confirmed, such a substance would be of
great use in the field of dentistry.
While oral premedication is effective enough for certain anxious patients to
receive dental treatment, there are a large number of people who are so highly anxious
that oral sedation is not adequate. For these people, they need to be under deep sedation
or general anesthesia in order to receive dental care. Due to the high level of anxiety in
these patients, even the insertion of an intravenous catheter or just the thought of being in
a dental clinic can be difficult for them. Therefore, even if deep sedation or a general
anesthetic is planned, an oral premedication may still be required for a number of these
types of patients in order to place an IV or to help them relax prior to general anesthesia.
Although this study examined the effectiveness of melatonin as a premedication for the
purpose of anxiety relief in patients undergoing a general anesthetic for dental treatment,
the results might also be applicable to patients receiving conventional dental treatment
who require a reduction in their anxiety.
Oral Sedation in Dentistry Because there are many people that have a significant degree of fear and anxiety
toward dental treatment, the use of an oral sedative has allowed them to receive needed
dental care. While the highly anxious or dental phobic patients may require a general
anesthetic for dental treatment, those who are mild to moderately anxious may be relaxed
enough through the use of an oral sedative.
5
By definition, an oral sedative is a drug that decreases activity, moderates
excitement, and calms the patient (Donaldson et al., 2007). These medications are safe
and help the majority of dental patients with mild to moderate anxiety to cope with their
fears and receive needed treatment. Taking medications orally is convenient, painless,
inexpensive, and widely accepted, especially by adult patients. For these reasons, oral
sedation can be beneficial in dentistry (Donaldson et al., 2007).
The evolution of sedative drugs started with fermented beverages used by
Sumerians around 9000 BC. The modern age of sedative medications started with
bromides and chloral hydrate in the 19th century. By the 20th century, barbiturates became
available and became a popular choice for oral sedation. Phenobarbital was the most
widely used barbiturate for sedative purposes. While barbiturates were effective at
sedation, they had certain undesirable side effects, such as potential for addiction,
cardiovascular and respiratory depression, and a low therapeutic index (Donaldson et al.,
2007). Barbiturate use was eventually replaced by benzodiazepines for sedation due to
their wide margin of safety and effectiveness in sedation, anxiolysis, and amnesia. Today,
they are the most widely used medication for oral sedation in dentistry (Donaldson et al.,
2007).
The type of medication to use for anxiolysis depends on the patient and the
procedure that is to be done. Elderly patients tend to be more sensitive to the sedative
effects of medications, so a lower dose than usual should be used. In patients with
cardiovascular, respiratory, renal or hepatic disease, the use of sedative medications
6
should be done carefully as to not exacerbate the existing medical condition. In children,
dosing should be done according to body weight and care need to be taken as to not
overdose the patient. The duration of action of the medications need to be considered
based on the length of the planned procedure so that the anxiolytic effects of the
medication do not wear off too quickly or that sedation is not prolonged after the
procedure is over (Donaldson et al., 2007).
Pharmacology of Melatonin
Melatonin is a naturally occurring hormone that is synthesized in many
vertebrates, including humans, and almost all invertebrates, bacteria, protozoa, plants,
and fungi (Hardeland et al., 2005). Thus, melatonin is a ubiquitous biomolecule present
in many living organisms. In humans, it is produced primarily by the pineal gland in the
brain from the amino acid tryptophan (Macchi and Bruce, 2004). Tryptophan is
hydroxylated into 5-hydroxytryptophan, then decarboxylated into serotonin, then
acetylated into N-acetylserotonin, which is methylated into melatonin, or N-acetyl-5-
methoxytryptamine (Naguib et al., 2007). The N-acetylation of serotonin is the rate-
limiting step. In mammals, the rate-limiting enzyme, arylalkylamine N-acetyltransferase,
is under the control of the suprachiasmatic nucleus, which is the circadian pacemaker.
Melatonin is not only present in the brain but also in other organs and cells, such as the
Harderian gland, the membranous cochlea, mononuclear leukocytes, skin, and the
gastrointestinal tract (Hardeland et al., 2005).
7
More than 90% of circulating melatonin is cleared by the liver (Caustrat et al.,
2005). Melatonin is metabolized in the liver by cytochrome P450 enzymes to 6-
hydroxymelatonin, which is then conjugated to form 6-sulfatoxymelatonin. This
metabolite is then excreted in the urine by the kidneys (Naguib et al., 2007). About 1% of
melatonin is excreted unchanged in the urine.
Melatonin has several functions in the human body, including regulating circadian
rhythms and the sense of the day-night cycle. Production of melatonin is stimulated by
darkness and inhibited by light, independent of sleep. Its production increases with
darkness, which is responsible for the onset of sleepiness. On average, the maximum
plasma level of melatonin occurs between the hours of 3:00 am to 4:00 am, and its
secretion is episodic with peaks and troughs. With light, its production is decreased to
undetectable levels so that the sense of sleepiness is lessened (Claustrat et al., 2005). It
appears that the amount of melatonin produced in humans differs not only with day-night
cycles, but with seasonal cycles as well. For example, more melatonin production has
been detected in the winter season as compared to the summer season (Calustrat et al.,
2005). This effect may be attenuated in modern societies due to extensive use of artificial
lighting and temperature control systems.
Melatonin activates many aspects of the immune system, such as B-cells, T-cells,
and monocytes, and causes the release of cytokines that modulate the immune system.
Melatonin has anti-inflammatory properties due to its inhibition of PGE2 and down-
regulation of COX-2 enzymes. Melatonin has also been shown to suppress cancer growth
8
and lower LDL and total cholesterol levels (Melatonin Monograph, 2005). This hormone
is also an antioxidant, as it scavenges free radicals, up-regulates antioxidant enzymes, and
down-regulates prooxidant enzymes. Melatonin is highly lipid soluble and can easily
cross cell membranes (Hardeland et al., 2005). The importance of melatonin in the human
body could be seen in patients who have undergone pinealectomy (surgical removal of
the pineal gland). Studies have shown that these people tend to have afternoon sleepiness,
mood disorders, visual and auditory hallucinations, and convulsive seizures (Claustrat et
al., 2005).
Melatonin has a hypnotic/sedative effect when administered orally (Melatonin
Monograph, 2005; Naguib et al., 2007). This may be due to its circadian rhythm
regulation effect. It is this property of melatonin that is of interest in anesthesia.
Melatonin appears to exert this effect in a way that is similar to other anaesthetic drugs:
by modulation of GABAA (gamma-aminobutyric acid) receptors in the brain (Hardeland
et al., 2006; Naguib et al., 2007) There are two types of melatonin receptors in the human
body: MT1 and MT2. Binding of melatonin to the MT1 receptor appears to affect the
GABAA receptor via the G-coupled protein pathway. This enhances the binding of
GABA to the GABAA receptor, which is similar to how other anaesthetic drugs, such as
propofol and benzodiazepines, exert their anesthetic effects (Naguib et al., 2007). GABA
is the primary inhibitory neurotransmitter in the brain. By enhancing GABA, this acts to
decrease the degree of neural activity, which is likely responsible for the induction of
anesthesia.
9
Exogenous melatonin is rapidly absorbed and peak plasma levels are reached in
60 to 150 minutes. The elimination half-life of melatonin is about 12-48 minutes. In the
bloodstream, 50-75% of melatonin is reversibly bound to albumin and alpha1-acid
glycoprotein, and its bioavailability from an oral dose ranges from 10-56% (Melatonin
Monograph, 2005). Circulating melatonin can reach all body tissues and crosses the
blood-brain barrier to modulate brain activity (Claustrat et al., 2005).
Melatonin appears to have very few side effects (Melatonin Monograph, 2005).
Isolated case reports mentioned psychomotor disturbances such as disorientation, fatigue,
headaches, irritability, and dizziness, and vivid dreams/nightmares in people who were on
melatonin supplements (Dollins et al., 1993; Suhner et al., 1998; Melatonin Monograph,
2005). There are reports that melatonin may increase the risk for seizures, especially with
those who have seizure disorders (Sheldon, 1998; Melatonin Monograph, 2005). Yet this
is controversial because other studies reported that melatonin actually decreased the
incidence of seizures (Fauteck et al., 1999; Siddiqui et al., 2001). There are studies which
indicate that melatonin may increase the risk of bleeding in people who are taking
warfarin. It is unknown whether the bleeding risk is significant in healthy people
(Lamberg, 1996; Melatonin Monograph, 2005). It should be noted that the doses needed
to induce these adverse reactions were significantly higher than the therapeutic doses.
Overall, melatonin is generally considered to be safe at the recommended doses for
sedation (Melatonin Monograph, 2005).
10
Measuring Anxiety The measurement of a person’s anxiety can be very subjective. Each person
experiences the same situation differently in many ways, and so the degree of anxiety that
is felt is also different from person to person. Anxiety is formed by a person’s
experiences, beliefs, method of reasoning, perceptions, and state of mind. As a result,
measuring one’s anxiety is not easily accomplished.
For the purposes of conducting studies, measuring anxiety could be accomplished
by either an observer or by the subjects themselves. There are standardized tests available
for both types that have been validated. Tests such as the State Trait Anxiety Inventory
and the Yale Preoperative Anxiety Scale involve a researcher observing the behaviour of
subjects and scoring their anxiety based on various factors (Kindler et al., 2000; Caumo
et al., 2001). Such tests do involve a certain degree of subjectivity, which is inherent to
the test itself.
Another test to measure anxiety is the Visual Analog Scale (VAS). This is a self-
assessment of anxiety where the subjects grade their own anxiety at the time of the test by
placing a vertical stroke along a horizontal line of a certain length, with one end
representing “no anxiety” and the other end representing “worst anxiety imaginable”.
Numerous studies have validated and verified the use of VAS to measure anxiety, and
this test has been used in other studies involving anxiety and melatonin.
11
Studies have shown that while each subject may rate the same situation very
differently in terms of the amount of anxiety that they are experiencing, the relative
degree of anxiety between situations is quite stable and reproducible (Tamiya et al., 2002;
Raat et al., 2004; Sherman et al., 2006). Therefore, one could use VAS to measure
anxiety relative to a certain situation, and then could use VAS again to measure anxiety
under a different situation and assess the change in anxiety, which is consistent from
person to person. This was the test used in this study.
Literature Review of Melatonin for Premedication
A review of the literature showed that the science on melatonin being used as a
premedication is relatively scarce. Since 1960, there appears to be only a handful of
articles that have investigated this topic. Therefore, it appears that the notion of melatonin
being used for sedation and anxiolysis prior to general anesthesia is a relatively new one.
In two studies by Naguib and Samarkandi (1999 and 2000), the administration of
sublingual melatonin prior to general anesthesia produced sedation and anxiolysis
comparable to that of sublingual midazolam in adult women, which was significantly
different compared to placebo. A VAS was used to assess anxiety. In the 1999 study, 5
mg of sublingual melatonin was used, and in the 2000 study doses of 0.05 mg/kg, 0.1
mg/kg, and 0.2 mg/kg of sublingual melatonin were used. The subjects who received
melatonin showed no significant impairment of cognitive or psychomotor skills, as
assessed by the Digit Symbol Substitution Test and the Trieger Dot Test.
12
In a study by Nava and Carta (2001), it was shown that 4-6 mg/kg of melatonin
reduced lipopolysaccharide-induced anxiety in male Sprague-Dawley rats. Ismail and
Mowafi (2009) found that in 40 patients undergoing cataract surgery, 10 mg of oral
melatonin premedication resulted in significantly reduced anxiety compared to placebo.
Acil et al. (2004) showed in a study that 5 mg sublingual melatonin produced sedation
and anxiolysis comparable to 15 mg sublingual midazolam in adults undergoing surgery
under general anesthesia.
Samarkandi et al. (2005) examined the use of orally administered melatonin and
midazolam compared to placebo in children undergoing minor surgery. The study found
that melatonin given at 0.25 mg/kg and 0.5 mg/kg orally were equally effective as
midazolam in alleviating anxiety in children for mask induction. They found that
melatonin was associated with faster recovery times and less incidence of postoperative
excitement and sleep disturbances 2 weeks postoperatively than with midazolam.
In another study involving children, Schmidt et al. (2007) reported that children
undergoing brainstem audiometry who received 5 mg (children up to one year of age), 10
mg (children between ages 1 to 6), or 20 mg (children older than 6 years of age) of oral
melatonin were sufficiently sedated for the purpose of the brain audiometry and avoided
the need for a general anesthetic for this procedure. In a separate study, Johnson et al.
(2002) examined the use of melatonin for the purpose of sedation in children undergoing
MRI. Administration of 10 mg of melatonin orally in children under the age of 4 resulted
in adequate sedation for this purpose.
13
There were also studies which showed that melatonin is generally safe to use
without significant adverse effects. Dollins et al. (1993) conducted a study involving the
administration of 10, 20, 40, and 80 mg of melatonin PO compared to placebo in 20
healthy male subjects. Numerous tests were done to assess for mood and performance
after its administration. They reported that the use melatonin caused fatigue, sleepiness,
decreased reaction time, and decreased vigour but otherwise there were no adverse
effects. Arendt (1997) reported that in normal, healthy adults over the age of 18 who are
not pregnant and without psychiatric disorders, the only significant short-term side effect
from oral administration of exogenous melatonin was sleepiness. The article reported that
consequences of long-term melatonin use were unknown.
From the review of scientific literature, it seems that melatonin has good potential
to be used for alleviating anxiety and producing sedation in patients undergoing general
anesthesia (comparable to benzodiazepines, the current gold standard), and melatonin
appears to be very safe to use without any significant adverse affects.
However, there have been studies which found that melatonin did not make a
significant difference in terms of sedation or anxiolysis. A study by Sury and Fairweather
(2006) examined the sedative effects of melatonin in children undergoing MRI. The
melatonin doses were 3 mg PO for children under 15 kg and 6 mg PO for children over
15 kg. They found that compared to placebo, melatonin did not contribute to sedation in
children for the purpose of MRI. Another study, by Isik et al. (2008), examined the
effects of oral melatonin versus oral midazolam and placebo as a premedication in
14
children undergoing dental treatment. The study used orally administered melatonin at 3
mg and 0.5 mg/kg, and compared this to 0.75 mg/kg of midazolam PO and placebo. They
found that melatonin was similar to that of placebo in sedation/anxiolysis and did not
contribute to the sedation of these children. In a study by Capuzzo et al. (2006), 71
subjects over the age of 65 scheduled for elective surgery were given 10 mg of melatonin
or placebo orally, and their anxiety levels were measured using a VAS. They found that
there was no significant difference in anxiolysis between melatonin and placebo in their
study. This study suggested that perhaps melatonin’s sedative/anxiolytic properties
diminish over age, and in the elderly its effects may be negligible.
These studies show that further investigation of melatonin as a potential
premedication is needed in order to determine its true effectiveness for this purpose. The
use of melatonin to alleviate anxiety for dental treatment has had very little investigation
in the scientific field, and a literature search failed to identify any studies done with
melatonin on adult dental patients.
Assessments Used In the Study Visual Analog Scale (VAS):
In clinical studies, a patient’s anxiety can be measured in a number of ways. One
well-established method is the use of a VAS, a validated scale which involves the patient
rating his/her anxiety by placing a mark on a straight line of a certain length (Kindler et
al., 2000; Caumo et al., 2001). One end of the line is “no anxiety” and the other end is
“worst anxiety possible”. Studies have shown that VAS within subjects is reliably
15
reproducible, so the use of a VAS is a valid method of anxiety measurement (Kindler et
al., 2000; Caumo et al., 2001). For this study, a 100 mm VAS was used. A baseline VAS
anxiety level was obtained, and this was compared to VAS anxiety values at different
time intervals (see Figure 1 for copy of the VAS used in the study).
Richmond Agitation Sedation Scale (RASS):
The sedative effects of melatonin were assessed by using the Richmond Agitation
Sedation Scale (Sessler et al., 2002). This is a validated scale in which an observer gives a
grade for sedation based on observations and interactions with the subjects. The grade
given is from +4 to –5. A grade of 0 indicates that the subject is calm and alert, while at
+4 the subject is combative and violent, and at –5 the subject is unarousable. Therefore,
the more sedated the subject is, the more negative the RASS score will be, and vice-versa
(see Figure 2 for copy of RASS used in the study).
Trieger Dot Test (TDT):
The degree of psychomotor impairment was assessed using the Trieger Dot Test
(see Figure 3 for copy of TDT used in the study). This validated test involves connecting
a series of dots to complete a particular shape. By having the subject complete this test
before and after administration of melatonin, the extent of psychomotor impairment can
be assessed by analyzing the number of dots missed, extraneous deviation of the lines,
and time required to complete the test (Trieger et al., 1969).
16
Digit Symbol Substitution Test (DSST): The degree of cognitive impairment was assessed using the Digit Symbol
Substitution Test (see Figure 4 for copy of DSST used in the study). The subject’s task in
this validated test was to draw in certain shapes that correspond to a set of numbers
within a certain time period. For this study, the time limit was for 60 seconds. By
completing this test before and after administration of melatonin, the extent of cognitive
impairment was assessed by comparing the number of questions that the subject got
correct (Hindmarch, 1980).
Quality of Recovery Questionnaire (QoR):
In order to assess the quality of recovery from anesthesia when melatonin was
used as a premedication, each subject was contacted by telephone 24 hours after each of
the trials to complete a Quality of Recovery Questionnaire (see Figure 5 for a copy of
QoR used in the study). This questionnaire consisted of five questions designed to assess
how well the subject recovered from the anesthetic from the day before. The subject was
to rank each question on a scale of 1 to 5, with 5 being the best and 1 being the worst
(Myles et al., 1999).
17
Figure 1
VAS EVALUATION FORM
PATIENT NUMBER DATE: Measure of Anxiety This is a means of recording the intensity of your anxiety. A mark at the
“no Anxiety” end of the scale means that you are currently not anxious
whatsoever. A mark toward the right along the line would mean gradually
increasing anxiety, until at the far right end your anxiety is considered to be the
worst possible. Please mark a stroke through the scale at the place appropriate
for your anxiety at this time.
| | No Anxiety Worst Anxiety imaginable
18
Figure 2
Figure 3
19
Trieger Dot Test
20
Figure 4
Digit Symbol Substitution Test
2 1 3 7 2 4 8 2 1 3 2 1 4 2 3 5 2 3 1 4 5 6 3 1 4
1 5 4 2 7 6 3 5 7 2 8 5 4 6 3 7 2 8 1 9 5 8 4 7 3
6 2 5 1 9 2 8 3 7 4 6 5 9 4 8 3 7 2 6 1 5 4 6 3 7
9 2 8 1 7 9 4 6 8 5 9 7 1 8 5 2 9 4 8 6 3 7 9 8 6
21
Figure 5
Quality of Recovery Questionnaire
On a scale of one (1) to five (5), please rate each of the questions, with 1 being the worst and 5 being the best.
(1) Feeling of general well-being
(2) Able to understand instructions; not confused
(3) Free from nausea, vomiting, or dizziness
(4) Good quality sleep, no bad dreams
(5) Able to perform at work normally
22
Statement of Purpose Because fear and anxiety are significant barriers to obtaining dental treatment for
many people, methods which effectively and safely reduce anxiety in such individuals are
a very important and valuable asset to the oral health of the general population. Currently,
the medications used to pharmacologically reduce anxiety have been effective, but not
without certain undesirable side effects and complications. An alternative medication
which increases the safety of its use and yet maintains a similar degree of anxiolytic
effectiveness would be very desirable.
The potential of melatonin to be used for this purpose has only recently been
examined. Early studies in medicine have shown that melatonin has good potential in
being used as a safe and effective anxiolytic premedication for patients undergoing
general anesthesia. Currently, there is no study which has examined the use of melatonin
as a premedication for adults in the field of dentistry. Should the potential of melatonin
be realized in its use as a premedication, it would be of great benefit to the dental
profession and to the community as a whole.
The purpose of this study was to examine the effectiveness of melatonin as a
premedication for anxious adult patients undergoing dental treatment under general
anesthesia. The study compared the hypnotic/sedative property of melatonin versus
placebo, the degree of anxiety relief, and the degree of cognitive and psychomotor
impairment. The quality of recovery from anesthesia was also assessed. In a double-
23
blind, randomized, cross-over study design, oral melatonin was administered and
compared to a placebo within the same subject.
Should melatonin show promise as a good premedication, further studies
comparing melatonin to benzodiazepines (such as triazolam or diazepam) could be
conducted to further examine its potential in the field of dentistry.
The objective of this study was to test the following Null Hypothesis (Ho): The
hypnotic/sedative effects of melatonin, when used as premedication in adult patients
undergoing dental treatment under general anesthesia, is no different from placebo in
alleviating their anxiety.
The specific objectives of the study were:
(1) To determine the sedative and anxiolytic effects of orally administered melatonin on
adults at time intervals of 30, 60 and 90 minutes.
(2) To determine the degree of psychomotor and cognitive impairment that may have
resulted from the administration of melatonin
(3) To determine the quality of recovery from the anesthetic administered with the
melatonin premedication
24
Methods This study received approval from the University of Toronto Research Ethics
Board. The site of the clinical study was at the Anesthesia Clinic at the Faculty of
Dentistry, University of Toronto. Subjects were chosen among the adult patients
receiving dental treatment under general anesthesia, based on the inclusion/exclusion
criteria. Initially, the exclusion criteria stated that patients under the age of 18 or over the
age of 65 and those who are taking sedative or CNS medications were ineligible for this
study. Afterwards, it was determined that these exclusion criteria were too strict and it
prevented the enrolment of a number of otherwise qualified subjects. Therefore, changes
were made to the inclusion/exclusion criteria such that subjects between the ages of 18 to
70 and subjects who were not taking benzodiazepines or barbiturates would be eligible
for the study. These changes were deemed to be appropriate for this study in terms of not
having a significant confounding effect on the study results. The amendment for these
changes was submitted to the Research Ethics Board, and its approval was received (see
Appendix 1 for copy of inclusion/exclusion criteria used in the study).
Inclusion Criteria: (1) In good health (ASA I or II) (2) Not taking benzodiazepines or barbiturates (3) Age 18-70 years, inclusive (4) Body weight between 40-120 kg, inclusive (5) Needing at least two dental appointments under anesthesia (6) Baseline VAS anxiety score of at least 40 mm (7) No seizure disorders (8) Not taking anticoagulant medication (9) Informed consent signed Exclusion Criteria: (1) ASA III or higher (2) Taking benzodiazepines or barbiturates (3) Age less than 18 years or over 70 years
25
(4) Body weight less than 40 kg or over 120 kg (5) Pregnancy (6) Needing less than two dental appointments (7) Baseline VAS anxiety score of less than 40 mm (8) Has seizure disorder (9) Taking anticoagulant medication (10) Informed consent not signed
During the anesthesia consultation session, eligible subjects were asked to
volunteer for this study, and those that agreed to do so were chosen. A consent form was
signed by each subject (see Appendix 2), after relevant information was given. An
information sheet was given to these subjects as well (see Appendix 3). To those subjects
who completed the study to its entirety, a gratuity of $50 was given to them. One
researcher was responsible for the collection of all data and its analysis.
Subjects whose baseline VAS anxiety score was at least 40 mm were asked to
participate in the study. The reason for this was because in order to have a valid
measurement of reduction in anxiety (based on the VAS), the subjects needed to initially
have a certain degree of anxiety. If a subject was not very anxious to begin with, any
reduction in anxiety due to the premedication would be more difficult to assess. It was
determined that if the initial VAS anxiety score is at least 40 mm, significant reduction in
anxiety could be validly measured.
Patients that were relatively healthy (ASA I or II) were chosen so that their
medical condition would not act as a confounding factor. Pregnant women were excluded
in order to avoid any unknown effects of melatonin on the fetus. Patients taking
benzodiazepines or barbiturates were excluded because these medications have anxiolytic
26
and sedative effects, which could confound the effect of melatonin in the study. Because
melatonin has been suspected of increasing the seizure threshold and enhancing the
effects of anticoagulants, patients who have seizure disorders or are taking anticoagulant
medications were excluded from the study. The age and body weight limits were used to
keep the subjects within the normal range in these categories to the general population.
The study took place during two of the subject’s anesthesia appointments. During
one of the appointments, oral melatonin was administered prior to their treatment under
general anesthesia. At the other appointment, an oral placebo was used. The study was
double blinded, so that neither the subject nor the researcher knew the identity or order of
the premedications. The randomization of the order of premedications (melatonin or
placebo) was done using a random numbers table generated by the SPSS 16.0 computer
program. The blinding of the study was done such that a third person not involved in the
study coded all of the premedications so that neither the subjects nor the researcher knew
the identity of any of the premedications that were given. The code was deciphered at the
end of the study by the researcher.
On the day of the anesthesia appointment, subjects completed a 100 mm VAS for
anxiety prior to being given the premedication in order to obtain a baseline value for
anxiety. The subject indicated on the 100 mm line how anxious he/she is at the moment
by marking it with a vertical line using a pen. Baseline heart rate, blood pressure, and
oxygen saturation levels were obtained at this time. The subject also completed a Trieger
Dot Test (TDT) and a Digit Symbol Substitution Test (DSST) in order to obtain baseline
27
values for psychomotor ability and cognitive skills, respectively. For the TDT, the subject
used a pen to connect a number of dots in order to complete the shape of the figure. For
DSST, the subject was given a time limit of 60 seconds to complete as much of the test as
possible by drawing in the shapes that corresponded to each digit.
Once these tests were completed, the subject was given either melatonin or a
placebo as a premedication. The pills were blinded as to the identity of these
preparations. Previous studies have suggested that 10 mg is an appropriate oral dose of
melatonin for an adult patient. It can be assumed that the average weight of these
patients is approximately 70 kg, which equates to 0.14 mg/kg. In order to take into
account the potential effect of the patients’ body weight, the amount of melatonin given
was determined by a sliding scale, such that subjects with a body weight between 40-59
kg received 7.5 mg, between 60-79 kg received 10 mg, between 80-99 kg received 12.5
mg, and between 100-120 kg received 15 mg. The placebo medication was composed of
an equivalent amount of lactose. These were taken orally with a small amount of water.
At time intervals of 30, 60, and 90 minutes after administration of the drug, each
subject completed a separate VAS for anxiety at each interval. Also, the level of sedation
was assessed using the Richmond Agitation Sedation Scale (RASS) at each time interval.
The subject’s heart rate, blood pressure, and oxygen saturation levels (SpO2) were also
measured and noted at each interval. In between the measurement times, the subjects
waited in a small, quiet room by themselves with the lights dimmed, away from the
28
dental environment, to maximize the anxiolytic effect of the drug and to promote
sedation.
Prior to receiving dental treatment under general anesthesia (90 minutes after
receiving melatonin or placebo), each subject completed the same TDT and DSST as
before. The subjects were then seen in order to receive their dental treatment. After 24
hours from their appointment, the subject was contacted by telephone to complete a
verbal Quality of Recovery questionnaire.
A sample size calculation was done to utilize data for anxiety, the primary
outcome measure. It involved level (type I error) of 0.05 and level (type II error) of
0.1. This was done in order to ensure that the results of the study would have a high
degree of power in order to detect differences between melatonin and placebo should a
difference exist. The difference in standard deviation of 12 between the test and
placebo groups was taken from previous studies on melatonin premedication that used
VAS to measure anxiety. A difference of 12 mm on a 100 mm VAS was considered to be
clinically significant, based on previous studies (Naguib and Samarkandi, 1999; Acil et
al., 2004). The sample size n was calculated according to the following formula:
n = (diff)
2 (1-/21-)2
diff n = (12)2 (1.96 + 1.28)2 (12)2
n = 11
29
After examining the adult patients at the Anesthesia Clinic at the Faculty of
Dentistry, University of Toronto, 12 subjects were enrolled in the study. Since this is a
cross-over design with each subject given both treatments, the 12 subjects each
completed two trials (one with melatonin and the other with placebo).
For each subject, data collection included the subject’s age, gender, body weight,
heart rate, blood pressure, and oxygen saturation. Heart rate and oxygen saturation was
measured using a pulse oximeter, and the blood pressure was measured using a BP cuff
and a stethoscope. Body weight was measured on a scale. Data was collected on the VAS
recordings, TDT results, DSST results, RASS results, and the 24-hour postoperative
Quality of Recovery questionnaire results.
The study had a time-course as follows: For Patients with a Morning Appointment:
8:00 am : Subject arrived at the Anesthesia Clinic. Instructions for the study were given.
8:05 am : Subject completed the VAS for anxiety, Trieger Dot Test, and Digit Symbol
Substitution Test. Heart rate, blood pressure, and SpO2 were measured.
8:15 am : Premedication was given orally with a small amount of water (melatonin or
placebo).
8:45 am : Subject completed VAS for anxiety. RASS (Richmond Agitation Sedation
Scale) was used to assess for sedation. Heart rate, blood pressure, and SpO2
were measured.
30
9:15 am : Subject completed VAS for anxiety. RASS was used to assess for sedation.
Heart rate, blood pressure, and SpO2 were measured.
9:45 am : Subject completed VAS for anxiety. RASS was used to assess for sedation.
Heart rate, blood pressure, and SpO2 were measured. Subject completed TDT
and DSST.
For Patients with Afternoon Appointment:
12:00 pm: Subject arrived at the Anesthesia Clinic. Instructions for the study were given.
12:05 pm: Subject completed the VAS for anxiety, Trieger Dot Test, and Digit Symbol
Substitution Test. Heart rate, blood pressure, and SpO2 were measured.
12:15 pm: Premedication was given orally with a small amount of water (melatonin or
placebo).
12:45 pm: Subject completed VAS for anxiety. RASS (Richmond Agitation Sedation
Scale) was used to assess for sedation. Heart rate, blood pressure, and SpO2
were measured.
1:15 pm : Subject completed VAS for anxiety. RASS was used to assess for sedation.
Heart rate, blood pressure, and SpO2 were measured.
1:45 pm : Subject completed VAS for anxiety. RASS was used to assess for sedation.
Heart rate, blood pressure, and SpO2 were measured. Subject completed TDT
and DSST.
31
Participants had the right to decide not to participate in the study or to withdraw at
any time without affecting their medical or dental care. All information related to this
clinical research study remained confidential. Names of participants or any other
information were not revealed in any of the reports or scientific publications related to
this study. Subjects were identified at all times by a study number only.
Only one investigator collected the data, and this data was placed in a secure
location at the Faculty of Dentistry, University of Toronto at all times.
Data Analysis
The data analysis performed was descriptive statistics, including mean values,
frequency distribution, and graphical displays of the dependent measure (VAS scores),
and those of the independent variables/covariates.
The primary outcome measure was the anxiety score as measured by the VAS.
The same subject was observed under two different conditions, and therefore the paired t-
test was the most appropriate test to compare the means of the VAS scores between the
melatonin and placebo trials to determine if any difference between the mean of the VAS
scores was statistically significant.
The mean difference in the subject’s heart rate, blood pressure, and oxygen
saturation (SpO2) between baseline and at each time interval for the melatonin and
placebo trials were also compared using a paired t-test to test for statistical significance
between the two trials.
32
The paired t-test was also used to assess the results for the RASS (test for
sedation). The mean RASS scores at each of the time intervals between the melatonin and
placebo trials were compared for statistical significance.
The mean difference in DSST score between the tests that were conducted prior to
administration of premedication and at the end of the study for the melatonin and placebo
trials were compared using the paired t-test, to determine the statistical significance
between the two trials.
The mean difference in the three aspects of the TDT (number of dots missed, line
deviations, and time to complete the test), between the tests conducted prior to
premedication and at the end of the study, were compared using the paired t-test for the
melatonin and placebo trials to determine statistical significance.
The mean scores for each of the five questions on the Quality of Recovery
Questionnaire (QoR) between melatonin and placebo trials were compared to each other
using the paired t-test to determine statistical significance.
In case the data from the study was not normally distributed, the non-parametric
equivalent of the paired t-Test, the Wilcoxon Signed Rank test, was also done on each of
the data set that was analyzed with the paired t-test. This was done to ensure that
33
statistical analysis would be accurately done regardless of whether the data distribution
was parametric or non-parametric.
For analysis of the mean values for the results of the melatonin trial alone, a one-
sample t-test was used to determine if the mean values from the melatonin trial were
statistically significant.
For each statistical analysis of the data, p < 0.05 was considered to be statistically
significant. The SPSS 16.0 computer program was used for all of the data analysis and
statistical calculations that were performed in this study.
Results After assessing the adult patients at the Faculty of Dentistry, University of
Toronto, 12 subjects were chosen based on the inclusion/exclusion criteria. These 12
subjects consented to the participation in the study, and the clinical trial was conducted
over two appointments for each subject. The amount of melatonin administered was done
according to the subject’s body weight. The 12 subjects included 8 females and 4 males.
The subject’s age ranged from 36 to 70 years (mean of 51.7 years) and the subject’s body
weight ranged from 45 to 109 kg (mean of 75.3 kg). The subject characteristic data are
shown in Table 1.
34
Table 1 : Subject Information
Category
Number (N)
Male 4 Female 8
Average Body Weight 75.3 kg (45-109) Average Age 51.7 years (36-70)
Melatonin 7.5 mg 3 Melatonin 10 mg 4
Melatonin 12.5 mg 4 Melatonin 15 mg 1
For the melatonin trial, the baseline VAS results for anxiety were subtracted from
the VAS scores completed at 30, 60, and 90 minutes after its administration. This would
indicate the degree of anxiety relief that melatonin provided. At the 30, 60, and 90 minute
intervals, the VAS value decreased by an average of 14.3 mm, 17.6 mm, and 21.0 mm,
respectively. These were all clinically significant results (see Table 2). One-sample t-test
results showed that these results were also statistically significant (p < 0.05).
The greatest reduction in the VAS score compared to baseline was at 30 minutes
for both melatonin and placebo trials (average of 14.3 mm and 12.7 mm, respectively).
The average reduction in VAS score between 30 and 60 minutes was 3.29 mm for
melatonin and 4.96 mm for placebo. Between 60 and 90 minutes, the average reduction
in VAS score was 3.37 mm and 0.25 mm for melatonin and placebo, respectively (see
Figure 6). For both 30-60 minute interval and 60-90 minute interval, the reduction of
VAS score for melatonin and placebo were not statistically significant, as shown by the
35
paired t-test. Therefore, the only significant reduction of VAS score occurred between 0
and 30 minutes (see Tables 3, 4, and 5).
The mean baseline VAS scores from the melatonin and placebo trials (at 0
minutes) were 61.7 mm and 66.8 mm, respectively. The paired t-test showed that there
was no statistically significant difference between these baseline VAS scores (see Table
6). This suggested that the results of this study were likely not significantly affected by
the regression to the mean effect. Therefore, the results from the melatonin and placebo
trials could be compared without adjusting for the regression to the mean effect.
In order to determine whether the reduction in VAS scores for the melatonin trial
were significant relative to that of placebo, the mean difference in VAS scores at the
three time intervals relative to baseline for the melatonin and placebo trials were
compared via the paired t-test. When these values were compared, the mean VAS
difference between melatonin and placebo were similar in value at all three time
intervals. The statistical analysis (paired t-test) indicated that there were no significant
differences between melatonin and placebo in VAS scores differences between baseline
and at all three time intervals (see Table 6 and Figure 7).
36
Table 2 : Outcome Results For Melatonin Trial Mean P-Value 95% CI VAS Difference From Baseline 0-30 Minutes 0-60 Minutes 0-90 Minutes
14.3 mm
17.6 mm
21.0 mm
0.041
0.014
0.015
(0.708, 27.9)
(4.31, 30.9)
(4.93, 37.1)
RASS Scores 30 Minutes 60 Minutes 90 Minutes
-0.25
-0.67
-0.67
0.191
0.005
0.005
(-0.64, 0.14)
(-1.08, -0.25)
(-1.08, -0.25)
DSST Score Difference From Baseline
-2.50
0.083
(-5.39, 0.39)
TDT Score Difference From Baseline Dots Missed Line Deviations Time to Complete
1.17
3.38 mm
-0.25 seconds
0.568
0.406
0.855
(-3.19, 5.53)
(-5.22, 12.0)
(-3.20, 2.70)
QoR Questionnaire Scores Question 1 Question 2 Question 3 Question 4 Question 5
4.58
4.42
5.00
4.83
4.58
0.000
0.000
0.000
0.000
0.000
(4.08, 5.09)
(3.91, 4.92)
-------------
(4.59, 5.08)
(4.16, 5.01)
37
Figure 6 : VAS Score For Melatonin and Placebo Trials
61.7
47.444.1
40.7
66.8
54.2
49.2 49.0
0
10
20
30
40
50
60
70
80
0 30 60 90
Time (minutes)
VA
S S
co
re (
mm
)
Melatonin
Placebo
* Error bars represent the Standard Error of the Mean
38
Table 3 : VAS Score Results For Melatonin and Placebo Trials Mean (mm) Standard Deviation (mm)
Melatonin 0 Minutes
30 Minutes
60 Minutes
90 Minutes
0-30 Minutes
0-60 Minutes
0-90 Minutes
61.7
47.4
44.1
40.7
14.3
17.6
21.0
22.4
28.2
29.2
30.7
21.4
20.9
25.3
Placebo 0 Minutes
30 Minutes
60 Minutes
90 Minutes
0-30 Minutes
0-60 Minutes
0-90 Minutes
66.8
54.2
49.2
49.0
12.7
17.6
17.9
25.0
32.9
33.6
30.5
17.8
23.7
18.6
39
Table 4 : VAS Results – Statistical Analysis For Melatonin Trial Melatonin
Firsta Melatonin Secondb
Mean Differencec
P-Valued 95% CIe
0-30 Minutes 61.7 47.4 14.3 0.041 0.708, 27.9 30-60 Minutes 47.4 44.1 3.29 0.058 -0.136, 6.72 60-90 Minutes 44.1 40.7 3.37 0.185 -1.87, 8.62 a: Mean value of VAS score for melatonin at first time interval (mm) b: Mean value of VAS score for melatonin at second time interval (mm) c: Difference between mean VAS score of first and second time interval (mm) d: Two-tailed P-value for Paired t-test e: 95% Confidence Interval (Lower Limit, Upper Limit) Table 5 : VAS Results – Statistical Analysis For Placebo Trial Placebo
Firsta Placebo Secondb
Mean Differencec
P-Valued 95% CIe
0-30 Minutes 66.8 54.2 12.7 0.031 1.37, 23.9 30-60 Minutes 54.2 49.2 4.96 0.095 -1.02, 10.9 60-90 Minutes 49.2 48.9 0.25 0.963 -11.2, 11.7 a: Mean value of VAS score for placebo at first time interval (mm) b: Mean value of VAS score for placebo at second time interval (mm) c: Difference between mean VAS score of first and second time interval (mm) d: Two-tailed P-value for Paired t-test e: 95% Confidence Interval (Lower Limit, Upper Limit)
40
Table 6 : VAS Results – Statistical Analysis Comparing Melatonin To Placebo
Mel Diffa Pla Diffb Mean Diffc P-Valued 95% CIe 0-30 Minutes 14.3 12.7 1.67 0.718 -8.23, 11.6 0-60 Minutes 17.6 17.6 0.00 1.000 -11.3, 11.3 0-90 Minutes 21.0 17.9 3.13 0.500 -6.74, 13.0 30-60 Minutes 3.29 4.96 -1.67 0.640 -9.29, 5.96 60-90 Minutes 3.38 0.25 3.13 0.566 -8.50, 14.8
Baseline 61.7 66.8 -5.12 0.189 -13.2, 2.92 a: Mean value of the VAS difference between first and second time interval for
melatonin trial (mm). Time 0 represents baseline. b: Mean value of the VAS difference between first and second time interval for
placebo trial (mm). Time 0 represents baseline. c: Difference between Mel Diff and Pla Diff (mm). Negative value means that the placebo result was greater than the melatonin result. d: Two-tailed P-value for Paired t-test e: 95% Confidence Interval (Lower Limit, Upper Limit)
41
To further assess the VAS results, a within-subject analysis was done. For this
analysis, the change in VAS at 30, 60, and 90 minutes relative to baseline was determined
for the melatonin and placebo trial, and then these differences were subtracted from each
other to determine the relative VAS difference of melatonin from placebo. The average
value of this difference was then compared to zero using the one-sample t-test (see Table
7). Figure 8 shows the result of this analysis. The difference between melatonin and
placebo was very small at 30, 60, and 90 minutes (1.67 mm, 0.00 mm, and 3.13 mm,
respectively), and were not clinically significant. Statistical analysis showed that there
were no significant differences between melatonin and placebo at any of the time
intervals.
In addition to the VAS, each subject’s heart rate, blood pressure, and oxygen
saturation (SpO2) were measured prior to administration of melatonin or placebo, and
also at each of the three time intervals (see Table 8, 9, and 10). In general, a subject’s
heart rate and blood pressure (especially systolic) tends to decrease with decreasing
anxiety, and vice versa.
42
Figure 7 : VAS Difference Relative To Baseline
-14.3
-17.6
-21.0
-12.7
-17.6 -17.9
-30
-25
-20
-15
-10
-5
030 60 90
Time (minutes)
VA
S S
co
re (
mm
)
MelatoninPlacebo
* Error bars represent the Standard Error of the Mean
43
Table 7 : Within-Subject VAS Analysis Subject Number
Difference Between VAS Change in Melatonin and VAS Change In Placebo At 30 Minutes (mm)
Difference Between VAS Change in Melatonin and VAS Change In Placebo At 60 Minutes (mm)
Difference Between VAS Change in Melatonin and VAS Change In Placebo At 90 Minutes (mm)
1 -7.0 -12.0 -21.5 2 5.0 -3.0 6.5 3 3.5 14.0 -1.0 4 -5.0 0.5 -9.5 5 -18.0 -34.5 20.5 6 10.0 22.5 12.0 7 -25.0 -22.5 -16.5 8 36.0 17.0 18.5 9 12.0 -8.0 -3.5 10 -3.0 -4.0 -2.5 11 2.0 8.0 3.5 12 9.5 22.0 31.0
Average 1.67 0.00 3.13 P-Value 0.718 1.000 0.500 95% CI -8.23, 11.6 -11.3, 11.3 -6.74, 13.0 * The VAS change refers to the difference between VAS score at 30, 60, and 90 minutes relative to the baseline VAS value. * A negative value means that the baseline VAS score was less than the VAS score at that particular time interval.
44
Figure 8 : Within-Patient Difference For VAS
0.00
3.13
1.67
-10
-8
-6
-4
-2
0
2
4
6
8
10
30 Minutes 60 Minutes 90 Minutes
VA
S S
co
re (
mm
)
* Error bars represent the Standard Error of the Mean
45
Table 8 : Heart Rate Results Mean Standard Deviation
Melatonin Baseline
30 Minutes
60 Minutes
90 Minutes
0-30 Minutes
0-60 Minutes
0-90 Minutes
77.4
72.9
71.2
72.7
4.50
6.25
4.75
13.7
10.4
11.0
9.83
7.07
5.54
10.3
Placebo Baseline
30 Minutes
60 Minutes
90 Minutes
0-30 Minutes
0-60 Minutes
0-90 Minutes
79.3
71.8
71.3
73.8
7.58
8.00
5.50
13.5
14.5
13.4
12.1
6.82
7.01
7.93
46
Table 9 : Blood Pressure Results Mean (mm Hg) Standard Deviation Melatonin Baseline Sys Dia 30 Minutes Sys Dia 60 Minutes Sys Dia 90 Minutes Sys Dia
116.7 77.5 113.3 77.5 114.2 77.1 112.9 75.0
11.9 7.83 10.1 6.91 10.6 8.65 12.5 8.53
Placebo Baseline Sys Dia 30 Minutes Sys Dia 60 Minutes Sys Dia 90 Minutes Sys Dia
118.8 78.8 115.0 77.5 115.0 76.7 114.2 76.3
16.4 9.08 13.5 8.12 15.7 9.37 17.9 8.82
47
Table 10 : Oxygen Saturation (SpO2) Results Mean (%) Standard Deviation
Melatonin Baseline
30 Minutes
60 Minutes
90 Minutes
98.0
97.4
97.9
97.7
0.603
0.900
0.900
1.07
Placebo Baseline
30 Minutes
60 Minutes
90 Minutes
97.1
97.2
96.9
97.7
1.68
2.21
2.23
0.985
*SpO2 was measured using a pulse oximeter
48
The mean heart rate prior to administration of melatonin or placebo (baseline
heart rate) was 77.4 for the melatonin trial and 79.3 for the placebo trial. In order to
estimate the degree of anxiety, the mean heart rates at 30, 60, and 90 minutes were
subtracted from the baseline heart rate to obtain the heart rate difference at each time
interval. For the melatonin trials, this mean difference in heart rate was 4.50, 6.25, and
4.75 for time intervals of 30, 60, and 90 minutes, respectively (see Table 11). The heart
rate difference at 60 minutes was statistically significant, as shown by the paired t-test.
For the placebo trial, the mean differences in heart rate were 7.58, 8.00, and 5.50 for 30,
60, and 90 minutes, respectively (see Table 12).
Similarly, the mean systolic blood pressure at baseline was determined to be
116.7 mm Hg for the melatonin trials and 118.8 mm Hg for the placebo trials. Again, the
mean systolic blood pressure at each of the three time intervals was subtracted from the
baseline value to obtain the systolic blood pressure difference, as an estimation of anxiety
relief. For the time intervals of 30, 60, and 90 minutes, the mean systolic blood pressure
differences for the melatonin trial were 3.33, 2.50, and 3.75 mm Hg, respectively (see
Table 14). None of these values were statistically or clinically significant. For the placebo
trial, the mean systolic blood pressure differences were 3.75, 3.75, and 4.58 mm Hg,
respectively (see Table 15).
49
Table 11 : Heart Rate – Statistical Analysis For Melatonin Melatonin
Firsta Melatonin Secondb
Mean Differencec
P-Valued 95% CIe
0-30 Minutes 77.4 72.9 4.50 0.050 0.011, 8.99 0-60 Minutes 77.4 71.2 6.25 0.002 2.73, 9.77 0-90 Minutes 77.4 72.7 4.75 0.138 -1.79, 11.3 30-60 Minutes 72.9 71.2 1.75 0.025 0.263, 3.24 60-90 Minutes 71.2 72.7 -1.50 0.394 -5.22, 2.22 a: Mean value of HR for melatonin at first time interval b: Mean value of HR for melatonin at second time interval c: Difference between mean HR of first and second time interval (negative value means that HR was greater at the second time interval than the first time interval) d: Two-tailed P-value for Paired t-test e: 95% Confidence Interval (Lower Limit, Upper Limit)
50
Table 12 : Heart Rate – Statistical Analysis For Placebo Placebo
Firsta Placebo Secondb
Mean Differencec
P-Valued 95% CIe
0-30 Minutes 79.3 71.8 7.58 0.003 3.25, 11.9 0-60 Minutes 79.3 71.3 8.00 0.002 3.55, 12.5 0-90 Minutes 79.3 73.8 5.50 0.035 0.464, 10.5 30-60 Minutes 71.8 71.3 0.417 0.846 -4.21, 5.04 60-90 Minutes 71.3 73.8 -2.50 0.080 -5.35, 0.348 a: Mean value of HR for placebo at first time interval b: Mean value of HR for placebo at second time interval c: Difference between mean HR of first and second time interval (negative value means that HR was greater at the second time interval than the first time interval) d: Two-tailed P-value for Paired t-test e: 95% Confidence Interval (Lower Limit, Upper Limit)
51
Table 13 : Heart Rate – Statistical Analysis Comparing Melatonin To Placebo Mel Diffa Pla Diffb Mean Diffc P-Valued 95% CIe 0-30 Minutes 4.50 7.58 -3.08 0.316 -9.54, 3.34 0-60 Minutes 6.25 8.00 -1.75 0.550 -8.11, 4.44 0-90 Minutes 4.75 5.50 -0.750 0.860 -9.91, 8.41 30-60 Minutes 1.75 0.420 1.33 0.509 -2.96, 5.63 60-90 Minutes -1.50 -2.50 1.00 0.687 -4.32, 6.32 a: Mean value of the HR difference between first and second time interval for
melatonin trial (negative value means that HR increased over that time interval). Time 0 represents baseline.
b: Mean value of the HR difference between first and second time interval for
placebo trial (negative value means that HR increased over that time interval). Time 0 represents baseline. c: Difference between Mel Diff and Pla Diff (negative value means that the placebo result was greater than the melatonin result) d: Two-tailed P-value for Paired t-test e: 95% Confidence Interval (Lower Limit, Upper Limit)
52
Table 14 : Systolic Blood Pressure – Statistical Analysis For Melatonin Melatonin
Firsta Melatonin Secondb
Mean Differencec
P-Valued 95% CIe
0-30 Minutes 116.7 113.3 3.33 0.180 -1.79, 8.46 0-60 Minutes 116.7 114.2 2.50 0.365 -3.33, 8.33 0-90 Minutes 116.7 112.9 3.75 0.145 -1.52, 9.02 30-60 Minutes 113.3 114.2 -0.833 0.615 -4.37, 2.71 60-90 Minutes 114.2 112.9 1.25 0.491 -2.61, 5.11 a: Mean value of SBP for melatonin at first time interval (mm Hg) b: Mean value of SBP for melatonin at second time interval (mm Hg) c: Difference between mean SBP of first and second time interval (mm Hg).
Negative value means that SBP was greater at the second time interval than the first time interval
d: Two-tailed P-value for Paired t-test e: 95% Confidence Interval (Lower Limit, Upper Limit)
53
Table 15 : Systolic Blood Pressure – Statistical Analysis For Placebo Placebo
Firsta Placebo Secondb
Mean Differencec
P-Valued 95% CIe
0-30 Minutes 118.8 115.0 3.75 0.043 0.134, 7.37 0-60 Minutes 118.8 115.0 3.75 0.005 1.36, 6.15 0-90 Minutes 118.8 114.2 4.58 0.067 -0.386, 9.55 30-60 Minutes 115.0 115.0 0.00 1.000 -3.32, 3.32 60-90 Minutes 115.0 114.2 0.833 0.740 -4.56, 6.22 a: Mean value of SBP for placebo at first time interval (mm Hg) b: Mean value of SBP for placebo at second time interval (mm Hg) c: Difference between mean SBP of first and second time interval (mm Hg) d: Two-tailed P-value for Paired t-test e: 95% Confidence Interval (Lower Limit, Upper Limit)
54
The magnitude of the differences in both heart rate and systolic blood pressure
between the melatonin and placebo trials was too small to be of clinical significance at all
three time intervals (see Figures 9 and 10). A paired t-test was done to compare the heart
rate and blood pressure differences at each time interval. The results showed that there
was no significant statistical difference at any of the time intervals for both heart rate and
systolic blood pressure differences (see Tables 13 and 16).
Between the 30 and 60 minute time intervals, the average change in heart rate was
1.75 for the melatonin trial, and 0.417 for the placebo trial. The average change in
systolic blood pressure was -0.833 mm Hg for the melatonin trial (negative sign means
that BP increased by 0.833 from 30-60 minutes), and 0.00 mm Hg for the placebo trial.
Between 60 and 90 minutes, the average change in heart rate was -1.50 for the melatonin
trial, and -2.50 for the placebo trial (again, the negative sign indicates an increase in heart
rate with time). The average change in systolic blood pressure was 1.25 mm Hg for the
melatonin trial, and 0.833 mm Hg for the placebo trials. Therefore, the change in heart
rate and systolic blood pressure for both the melatonin and placebo trials at each time
interval was small and not clinically significant. Statistically (using the paired t-test), only
the change in HR between 30-60 minutes for melatonin was significant at p < 0.05.
Between the melatonin and placebo trials, the average difference in the change in
HR was 1.33 for 30-60 minutes, and 1.00 for 60-90 minutes. The average difference in
systolic BP changes between melatonin and placebo was -0.833 mm Hg (placebo had a
greater reduction in BP than melatonin) at 30-60 minutes and 0.417 mm Hg at 60-90
55
Figure 9 : Average Heart Rate Differences
-4.50
-6.25
-4.75
-7.58-8.00
-5.50
-15
-13
-11
-9
-7
-5
-3
-1 30 60 90
Time (Minutes)
Hea
rt R
ate
MelatoninPlacebo
* Error bars represent the Standard Error of the Mean
56
Figure 10 : Average Systolic Blood Pressure Differences
-3.33
-2.50
-3.75-3.75 -3.75
-4.58
-10
-9
-8
-7
-6
-5
-4
-3
-2
-1
030 60 90
Time (Minutes)
Syst
olic
Blo
od P
ress
ure
(m
m H
g)
MelatoninPlacebo
* Error bars represent the Standard Error of the Mean
57
Table 16 : Systolic Blood Pressure – Statistical Analysis Comparing Melatonin To Placebo
Mel Diffa Pla Diffb Mean Diffc P-Valued 95% CIe 0-30 Minutes 3.33 3.75 -0.417 0.901 -7.64, 6.81 0-60 Minutes 2.50 3.75 -1.25 0.699 -8.17, 5.67 0-90 Minutes 3.75 4.58 -0.833 0.806 -8.11, 6.44 30-60 Minutes -0.833 0.00 -0.833 0.689 -5.29, 3.63 60-90 Minutes 1.25 0.833 0.417 0.889 -6.00, 6.84 a: Mean value of SBP difference between the first and second time interval for
melatonin trial (mm Hg). Time 0 represents baseline. Negative value means that SBP was greater at the second time interval than the first time interval.
b: Mean value of SBP difference between the first and second time interval for placebo trial (mm Hg). Time 0 represents baseline. c: Difference between Mel Diff and Pla Diff (mm Hg). Negative value means that the placebo result was greater than the melatonin result. d: Two-tailed P-value for Paired t-test e: 95% Confidence Interval (Lower Limit, Upper Limit)
58
minutes. Again, these differences between melatonin and placebo were too small to be
clinically significant. Paired t-tests showed that there were no significant differences
between melatonin and placebo in terms of HR or SBP differences at 30-60 minutes or
60-90 minutes (see Tables 13 and 16).
The level of oxygen saturation (SpO2) was assessed to determine if melatonin
impacted SpO2 levels over time if used as a premedication. For melatonin, the average
baseline SpO2 level was 98.0%. At 30, 60, and 90 minutes, the average SpO2 value were
97.4%, 97.9%, and 97.7%, respectively. For placebo, the baseline SpO2 value was 97.1%.
At 30, 60, and 90 minutes, the SpO2 values were 97.2%, 96.9%, and 97.7%, respectively
(see Figure 11). The difference between baseline SpO2 and that at 30, 60, and 90 minutes
were all very small (less than 1%) for both melatonin and placebo. When the difference
in SpO2 between baseline and the three time intervals were compared between melatonin
and placebo, the values were very small at all three time intervals and were not clinically
or statistically significant (see table 17).
The result of the RASS for the melatonin trial showed that the mean RASS scores
at 30, 60, and 90 minutes were –0.25, -0.67, and –0.67, respectively (see Table 2). The
one-sample t-test showed that the results at 60 and 90 minutes were statistically
significant. These results were also clinically significant, as the mean scores were close to
–1, which corresponded to “drowseness” on the RASS.
59
Figure 11 : Average Oxygen Saturation (SpO2)
98.0
97.4
97.9
97.7
97.197.2
96.9
97.7
95
95.5
96
96.5
97
97.5
98
98.5
99
99.5
100
0 30 60 90
Time (minutes)
Ox
yg
en
Sa
tura
tio
n (
%)
MelatoninPlacebo
* Error bars represent the Standard Error of the Mean
60
Table 17 : SpO2 Results – Statistical Analysis Comparing Melatonin To Placebo Mel Diffa Pla Diffb Mean Diffc P-Valued 95% CIe 0-30 Minutes 0.58 -0.08 0.667 0.194 -0.394, 1.73 0-60 Minutes 0.08 0.17 -0.083 0.809 -0.823, 0.657 0-90 Minutes 0.33 -0.58 0.917 0.085 -0.149, 1.98
a: Mean value of the difference between baseline SpO2 and SpO2 at each time interval for melatonin trial (%) b: Mean value of the difference between baseline SpO2 and SpO2 at each time interval
for placebo trial (%). Negative value means that SpO2 at that time interval was greater than baseline SpO2.
c: Difference between Mel Diff and Pla Diff (%). Negative value means that the placebo result was greater than the melatonin result. d: Two-tailed P-value for Paired t-test e: 95% Confidence Interval (Lower Limit, Upper Limit)
61
The mean values of the RASS scores were compared between the melatonin and
placebo trials at the three time intervals to determine if any significant differences existed
between them. The mean RASS score for the placebo trial at 30, 60, and 90 minutes were
-0.17, -0.33, and -0.25, respectively (see Table 18). The difference between melatonin
and placebo trials for mean RASS scores at all three time intervals was very small
(-0.083, -0.333, and -0.417 for 30, 60, and 90 minutes, respectively), and the differences
were not clinically significant. The paired t-test showed that the only significant
difference was at time interval of 60 minutes (p < 0.05); at the other two time intervals
the difference between the melatonin and placebo trials were not statistically significant
(see Table 19 and Figure 12).
The difference in RASS scores between 30-60 minutes and between 60-90
minutes were also examined to determine at which time interval the greatest degree of
sedation took place. For the melatonin trial, the mean RASS score difference between 30-
60 minutes was -0.42, and between 60-90 minutes was 0.00. Therefore, it seemed that the
greatest degree of sedation for the melatonin trial occurred between 30-60 minutes (see
Table 19). For the placebo trial, the mean RASS score difference between 30-60 minutes
was -0.17, and between 60-90 minutes was 0.083 (sedation lessened between 60-90
minutes). When the RASS score differences between 30-60 minutes and 60-90 minutes
for the melatonin and placebo trials were compared, this difference was only -0.250 for
30-60 minutes and -0.083 for 60-90 minutes. In both cases the difference was very small
and not clinically significant. The paired t-test results showed that there was no
significant difference between the mean RASS score differences for the melatonin and
62
Table 18 : Richmond Agitation Sedation Scale Results Mean Standard Deviation
Melatonin 30 Minutes
60 Minutes
90 Minutes
-0.25
-0.67
-0.67
0.622
0.651
0.651
Placebo 30 Minutes
60 Minutes
90 Minutes
-0.17
-0.33
-0.25
0.389
0.651
0.754
Table 19 : RASS Results – Statistical Analysis Mel Diffa Pla Diffb Mean Diffc P-Valued 95% CIe 0-30 Minutes -0.25 -0.17 -0.083 0.339 -0.267, 0.100 0-60 Minutes -0.67 -0.33 -0.333 0.039 -0.646, -0.02 0-90 Minutes -0.67 -0.25 -0.417 0.096 -0.920, 0.087 30-60 Minutes -0.42 -0.17 -0.250 0.191 -0.645, 0.145 60-90 Minutes 0.00 0.083 -0.083 0.723 -0.587, 0.420 *At time 0 minutes, RASS score was 0 (baseline) for Melatonin and Placebo a: Mean value of the RASS score at each time interval for melatonin trial b: Mean value of the RASS score at each time interval for placebo trial c: Difference between mean RASS score of melatonin and placebo at each time interval (negative value means that the melatonin result was greater than the placebo result) d: Two-tailed P-value for Paired t-test e: 95% Confidence Interval (Lower Limit, Upper Limit)
63
Figure 12 : RASS Score Results
-0.25
-0.67 -0.67
-0.17
-0.33
-0.25
-1
-0.9
-0.8
-0.7
-0.6
-0.5
-0.4
-0.3
-0.2
-0.1
0
30 60 90
Time (minutes)
RA
SS
Sc
ore
MelatoninPlacebo
* Error bars represent the Standard Error of the Mean
64
placebo trials between 30-60 minutes and between 60-90 minutes.
The degree of cognitive impairment from melatonin administration was assessed
using the Digit Symbol Substitution Test (DSST). The baseline DSST score was
subtracted from the DSST score at 90 minutes after administration of premedication in
order to determine the degree of cognitive impairment between these two conditions. For
the melatonin trial, this difference in DSST score was –2.50 (negative sign meant that on
average subjects did better on the DSST after 90 minutes than prior to premedication).
This was not a statistically significant result, as shown by the one sample t-test (see Table
2). The mean values of the DSST score difference for the melatonin and placebo trials
were compared to determine if any significant difference was present between them (see
Table 20). The mean DSST score difference for the melatonin trial was -2.50, and for the
placebo trial was -1.83. Again, this difference between melatonin and placebo was very
minimal and not clinically significant. The paired t-test results showed that there was no
significant statistical difference between the melatonin and placebo trials between
baseline and at 90 minutes (see Table 21 and Figure 13).
In order to measure the degree of psychomotor impairment from melatonin
administration, the Trieger Dot Test (TDT) was used. Three aspects of the TDT were
examined: the number of dots missed, magnitude of line deviations, and time required to
complete the test (see Table 22). Higher the value of these factors, the greater the degree
of psychomotor impairment this will indicate. Once these three factors were assessed, the
65
Table 20 : Digit Symbol Substitution Test Results
Baseline Score End Score Differencea Melatonin 28.1 30.6 -2.50
Placebo 28.3 30.2 -1.83 a : Negative value means that placebo was greater than melatonin * Mean values are given in each case Table 21 : DSST Results – Statistical Analysis
Mel Diffa Pla Diffb Mean Diffc P-Valued 95% CIe DSST -2.50 -1.83 -0.667 0.694 -4.31, 2.97
a: Mean value of the Difference between Digit Symbol Substitution Test scores for
melatonin trial between baseline and 90 minutes after administration (negative value means that the DSST score after 90 minutes was greater than that at baseline)
b: Mean value of the Difference between Digit Symbol Substitution Test scores for
placebo trial between baseline and 90 minutes after administration (negative value means that the DSST score after 90 minutes was greater than that at baseline)
c: Difference between Mel Diff and Pla Diff (negative value means that the placebo result was greater than the melatonin result) d: Two-tailed P-value for Paired t-test e: 95% Confidence Interval (Lower Limit, Upper Limit)
66
Figure 13 : Digit Symbol Substitution Test (DSST) Results
28.1
30.6
2.5
28.3
30.2
1.83
0
5
10
15
20
25
30
35
40
Baseline End Difference
DS
ST
Sco
re
MelatoninPlacebo
67
Table 22 : Trieger Dot Test Results Baseline Score End Score Differencea
Melatonin Dots Missed
Line Deviations (mm)
Time to Compete (sec)
12.8
48.0
19.7
13.9
51.4
19.5
1.17
3.38
-0.25
Placebo Dots Missed
Line Deviations (mm)
Time to Complete (sec)
12.8
49.3
21.2
14.0
46.8
18.5
1.25
-2.46
-2.68
a : Negative value means that End Score was greater than Baseline Score * Mean values are given in each case
68
value of these factors from the TDT completed at baseline were subtracted from the value
of TDT completed at 90 minutes post-administration of melatonin or placebo to
determine the difference in TDT results between these two time intervals. For the
melatonin trial, the mean difference in missed dots was 1.17, the mean difference in line
deviations was 3.38 mm, and the mean difference in time to finish was -0.25 seconds.
The one-sample t-test results showed that none of the three aspects of the TDT for the
melatonin trial were statistically significant (see Table 2). For the placebo trial, the mean
differences were 1.25, -2.46 mm, and -2.68 seconds, respectively (the negative sign
meant that the subjects did better at these aspects of the TDT after receiving melatonin or
placebo than prior to their administration). The difference between dots missed, line
deviations, and time to complete the test between the melatonin and placebo trials were
very small, and not clinically significant. The paired t-test results confirmed that there
was no significant difference between the melatonin and placebo groups in any of missed
dots, line deviations, or time to complete the test (see Table 23 and Figure 14).
A Quality of Recovery questionnaire was complete for each subject 24 hours after
the completion of each trial with both melatonin and placebo. This was done over the
telephone. The Questionnaire consisted of 5 questions, with each question being scored
on a scale of 1 (lowest) to 5 (highest). The mean values of the scores for questions 1
through 5 for the melatonin trial were 4.58, 4.42, 5.00, 4.83, and 4.58, respectively. The
one-sample t-test results showed that the mean values for all five questions were
statistically significant (see Table 2). For the placebo trial, the mean score values were
4.17, 4.17, 4.75, 4.42, and 4.33, respectively. Therefore, the difference in the QoR scores
69
Table 23 : TDT Results – Statistical Analysis Mel
Diffa Pla
Diffb Mean Diffc P-Valued 95% CIe
Dots Missed
1.17 1.25 -0.083 0.977 -6.19, 6.03
Line Deviations (mm)
3.38 -2.46 5.83 0.341 -7.07, 18.7
Completion Time (sec)
-0.25 -2.68 2.43 0.219 -1.67, 6.53
a: Mean value of the Difference between Trieger Dot Test scores for melatonin trial (negative value means that End Score was greater than Baseline Score) b: Mean value of the Difference between Trieger Dot Test scores for placebo trial (negative value means that End Score was greater than Baseline Score) c: Difference between Mel Diff and Pla Diff (negative value means that the placebo result was greater than the melatonin result) d: Two-tailed P-value for Paired t-test e: 95% Confidence Interval (Lower Limit, Upper Limit)
70
Figure 14 : Trieger Dot Test (TDT) Results
1.17
3.38
-0.25
1.25
-2.46 -2.68
-10
-8
-6
-4
-2
0
2
4
6
8
10
Dots MissedDifference
Line DeviationsDifference (mm)
Time to CompleteDifference (seconds)
MelatoninPlacebo
71
between the two trials was very small and not of clinical significance. The results of the
paired t-test showed that there were no significant differences between any of the five
questions of the Quality of Recovery Questionnaire between the melatonin and placebo
trials (see Tables 24 and 25; see Figure 15). The question that received the highest
average score was question 3 (concerning dizziness, nausea, and vomiting), for both
melatonin and placebo. The question that received the lowest score was question 2 for
melatonin (concerning ability to understand instructions and not be confused) and
questions 1 and 2 for placebo (tie).
The paired t-tests that were performed in this study to compare the means of
various factors between the melatonin and placebo trials were done on the assumption
that these data were parametric, meaning that the data was normally distributed. In the
case that this data was not normally distributed, a non-parametric equivalent of the paired
t-test, the Wilcoxon Signed Rank test, was performed on the main factors that underwent
the paired t-test analysis for significance. In all cases, the results of the Wilcoxon Signed
Rank test showed no significant difference at p < 0.05 between any of the factors that
were compared, except for the mean difference in RASS score between melatonin and
placebo at 60 minutes (which the paired t-test also showed as being significant). Table 26
shows the results of the Wilcoxon Signed Rank test for each of the mean values that were
compared with the paired t-test.
In order to assess for the effect of learning on the DSST and TDT, the results of
these tests were analyzed based on the order of the trials (first and second) regardless of
the premedication used during these trials. For the DSST, the baseline and end test scores
72
Table 24 : Quality of Recovery Questionnaire Results Mean Standard Deviation
Melatonin Question 1
Question 2
Question 3
Question 4
Question 5
4.58
4.42
5.00
4.83
4.58
0.793
0.793
0.000
0.389
0.669
Placebo Question 1
Question 2
Question 3
Question 4
Question 5
4.17
4.17
4.75
4.42
4.33
1.27
1.19
0.866
1.08
1.07
73
Table 25 : Quality of Recovery Questionnaire Results – Statistical Analysis
Mel Diffa Pla Diffb Mean Diffc P-Valued 95% CIe Question 1 4.58 4.17 0.417 0.295 -0.417, 1.25 Question 2 4.42 4.17 0.250 0.571 -0.693, 1.19 Question 3 5.00 4.75 0.250 0.339 -0.300, 0.800 Question 4 4.83 4.42 0.417 0.210 -0.272, 1.11 Question 5 4.58 4.33 0.250 0.463 -0.473, 0.973
a: Mean value of the QoR Questionnaire score for melatonin trial b: Mean value of the QoR Questionnaire score for placebo trial c: Difference between mean QoR Questionnaire score between melatonin and placebo trials d: Two-tailed P-value for Paired t-test e: 95% Confidence Interval (Lower Limit, Upper Limit)
74
Figure 15 : Quality of Recovery Questionnaire (QoR) Results
4.584.42
5.004.83
4.58
4.17 4.17
4.75
4.424.33
0
1
2
3
4
5
6
Question1
Question2
Question3
Question4
Question5
Qo
R S
core
MelatoninPlacebo
75
Table 26 : Wilcoxon Signed Rank Test Results Mean Rank
(negative, positive) Sum of Ranks
(negative, positive) P-Value
VAS : 30 Minutes Melatonin – Placebo
6.70 , 6.36
33.50 , 44.50 0.667
VAS : 60 Minutes Melatonin – Placebo
6.33 , 6.67 38.00 , 40.00 0.937
VAS : 90 Minutes Melatonin – Placebo
5.25 , 7.75 31.50 , 46.50 0.556
RASS : 30 Minutes Melatonin – Placebo
1.00 , 0.00 1.00 , 0.00 0.317
RASS : 60 Minutes Melatonin – Placebo
2.50 , 0.00 10.00 , 0.00 0.046
RASS : 90 Minutes Melatonin – Placebo
3.60 , 3.00 18.00 , 3.00 0.096
DSST : Differences Melatonin – Placebo
5.31 , 8.88 42.50 , 35.50 0.783
TDT : Dots Missed Melatonin – Placebo
4.17 , 6.67 25.00 , 20.00 0.766
TDT : Line Dev Melatonin - Placebo
7.25 , 6.12 29.00 , 49.00 0.432
TDT : Time Melatonin – Placebo
4.80 , 7.71 24.00 , 54.00 0.239
QoR : Question 1 Melatonin – Placebo
1.00 , 2.50 1.00 , 5.00 0.285
QoR : Question 2 Melatonin – Placebo
3.00 , 5.33 12.00 , 16.00 0.726
QoR : Question 3 Melatonin – Placebo
0.00 , 1.00 0.00 , 1.00 0.317
QoR : Question 4 Melatonin – Placebo
1.50 , 2.83 1.50 , 8.50 0.197
QoR : Question 5 Melatonin - Placebo
1.50 , 3.50 3.00 , 7.00 0.461
Heart Rate : 30 Min Melatonin – Placebo
6.31 , 6.88 50.50 , 27.50 0.366
Heart Rate : 60 Min Melatonin – Placebo
7.25 , 5.75 43.50 , 34.50 0.724
Heart Rate : 90 Min Melatonin – Placebo
6.75 , 5.57 27.00 , 39.00 0.590
SBP : 30 Minutes Melatonin – Placebo
5.33 , 3.00 16.00 , 12.00 0.731
SBP : 60 Minutes Melatonin - Placebo
5.00 , 6.25 30.00 , 25.00 0.797
SBP : 90 Minutes Melatonin - Placebo
7.75 , 4.00 31.00 , 24.00 0.719
76
from the first trial were compared to that of the second trial. For the TDT, the baseline
and end values of the three aspects of the test (dots missed, line deviations, and time to
complete the test) of the first and second trials were compared. Table 27 and Figures 16
and 17 show the results of this comparison. For the DSST, the scores for both baseline
and end test were higher on average during the second trial than the first. The difference
in the baseline score was 5.08, and for the end score it was 1.92. Statistically, the
difference between the baseline scores was significant (p < 0.05), while the end score
difference was not statistically significant by a slim margin (p = 0.051). For the TDT, the
difference in baseline scores between the first and second trials for dots missed, line
deviations, and time to complete were 0.167, 4.08 mm, and –1.25 seconds, respectively
(negative sign meant that the value of the first trial was higher than that of the second
trial). The difference in the end scores between the first and second trials were 0.083,
6.83 mm, and -2.33 seconds, respectively. Of these, only the line deviation results (for the
baseline and end scores) between the first and second trial seemed to be of clinical
significance. The other differences in scores were very small and not clinically
significant. The paired t-test results showed that there was no statistical significance for
any of the comparisons between first and second trials for the TDT.
77
Table 27 : DSST and TDT Score Comparison Between First and Second Trials Baseline
Score First Trial
Baseline Score
Second Trial
End Score First Trial
End Score
Second Trial
Baseline Score
Difference
P-Value Baseline
End Score Difference
P-ValueEnd
DSST Results
25.7
30.8
29.4
31.3
5.08
0.001
1.92
0.051
TDT: Dots Missed
12.8
12.7
14.0
13.9
0.167
0.933
0.083
0.963
TDT: Line Deviation (mm)
50.7
46.6
52.5
45.7
4.08
0.313
6.83
0.202
TDT: Time to Complete (seconds)
19.9
21.1
18.2
20.6
-1.25
0.505
-2.33
0.114
78
Figure 16 : Average DSST Scores For First and Second Trials
25.7
29.430.8 31.3
0
5
10
15
20
25
30
35
40
Baseline End
DS
ST
Sco
re
FirstSecond
79
Figure 17 : Average TDT Results For First and Second Trials
12.814.0
50.752.5
19.918.2
12.713.9
46.645.7
21.1 20.6
0
10
20
30
40
50
60
Dots MissedBaseline
Dots MissedEnd
LineDeviationsBaseline
LineDeviations
End
Time ToCompleteBaseline
Time ToComplete
End
TD
T V
alu
es
FirstSecond
80
Discussion Melatonin’s hypnotic/sedative properties when taken exogenously led to the
postulation that melatonin administered orally could potentially be used for anxiolysis
and sedation in treating anxious dental patients. The limited number of studies which had
examined this potential had showed mixed results, with some reporting that melatonin
had good anxiolytic properties while others have found that melatonin was not effective
in relieving anxiety. This study attempted to further examine melatonin’s potential for
sedation and anxiolysis, in adult dental patients undergoing general anesthesia for dental
treatment.
In this study, anxiety was assessed using a VAS where the subjects assessed their
own anxiety at baseline and at 30, 60, and 90 minutes after administration of melatonin or
placebo. There was a significant reduction in anxiety (as shown by the reduction in VAS
scores) at 30 minutes after melatonin administration. The reduction in anxiety continued
at 60 and 90 minutes after administration, but the degree of the reduction was relative
small compared to that at 30 minutes. Therefore, it appeared that the greatest and most
clinically significant decrease in anxiety with melatonin occurred 30 minutes after its
administration.
When the VAS scores for the melatonin trial at the 30, 60, and 90 minute intervals
were compared to baseline, the reduction in VAS score at each time interval was
statistically and clinically significant. This result showed that melatonin had potential to
be used to decrease anxiety levels of dental patients.
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However, when the results from the placebo trial were compared to the melatonin
trial, the VAS score differences at the three time intervals compared to baseline showed
no significant differences between the melatonin and placebo trials. The difference in
anxiety reduction from melatonin was slightly greater than that of placebo at 30 minute
and 90 minute, while at 60 minutes there was no difference. Statistically, there were no
significant differences between the melatonin and placebo trials at any of the three time
intervals. Therefore, when compared to placebo, melatonin did not seem to show a
significant difference in terms of VAS measurement for anxiety, at any of the three time
intervals.
Other indirect methods of determining anxiety reduction are to examine changes
in heart rate and blood pressure. With increasing anxiety, a subject’s heart rate and blood
pressure (especially systolic) tend to increase as well, and vice-versa. This is because fear
and anxiety elicits the sympathetic nervous system, or the so-called “fight-or-flight”
system. One of the effects of the sympathetic nervous system is to increase heart rate and
systolic blood pressure. In fact, increases in heart rate and blood pressure are among the
signs used to detect inadequate depth of anesthesia by anesthesiologists. Therefore, the
difference in heart rate and systolic blood pressure at the three time intervals of the study
compared to the baseline value would be an indication of a subject’s level of anxiety,
with higher levels being related to higher degrees of anxiety.
The change in heart rate relative to baseline for the melatonin trial was
statistically and clinically significant at the 30 and 60 minute time intervals, which
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suggested that melatonin may possess anxiolytic properties. However, the difference in
heart rate and systolic blood pressure at all three time intervals compared to baseline for
the melatonin and placebo trials were very similar and not statistically significant. Thus,
although the results of the melatonin trial indicated its potential to be used for anxiolysis,
melatonin did not appear to decrease anxiety to a significant extent when compared to
placebo, based on heart rate and blood pressure.
Furthermore, the average changes in heart rate and blood pressure between the
time intervals (0-30 minutes, 30-60 minutes and 60-90 minutes) for both the melatonin
and placebo trials were also very small and were not of clinical or statistical significance.
This showed that melatonin had little effect on heart rate and blood pressure changes
relative to placebo throughout the duration of 90 minutes after its administration. This
further indicated that at the doses used in this study, melatonin appeared to have little
effect in calming the subjects and reducing anxiety compared to placebo. However, it
should be noted that there are significant individual variations in heart rate and blood
pressure such that the correlation between these parameters and anxiety may not be very
accurate in some individuals. Thus, even though the changes in heart rate and blood
pressure were minimal, this in itself does not mean that anxiety was similarly unaffected.
The level of SpO2 was assessed in this study to determine if the use of melatonin
negatively affected the patient’s ability to intake oxygen. This may be possible if the
effectiveness of breathing is decreased or if cardiac output is impaired. The results
showed that SpO2 difference from baseline and at 30, 60, and 90 minutes were very small
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and was not clinically or statistically significant. When compared to placebo, melatonin
showed no difference in SpO2 changes at all three time intervals. Therefore, it appears
that the use of melatonin as an oral premedication did not affect the patient’s oxygen
saturation levels. This result suggested that breathing and circulation were not
significantly affected by the use of melatonin.
To assess for the degree of sedation between the melatonin and placebo trials, the
RASS was used at each of the three time intervals. The score in RASS is such that the
more negative the score value is, the greater the degree of sedation, and vice-versa. When
the mean RASS scores for the melatonin trial were examined, the results at 60 and 90
minutes were statistically and clinically significant. This indicated that melatonin had the
potential to be used as an oral sedative. However, the average RASS score difference
between melatonin and placebo trials at all three time intervals was less than 0.5, a very
minimal difference. In RASS, a score of 0 indicates alert and calm, while a score of -1
indicates drowsiness. So, differences of less than 0.5 would be considered insignificant.
The paired t-test and Wilcoxon Signed Rank Test showed that only the RASS difference
at time 60 minutes was statistically significant (p < 0.05). However, because the
difference was only 0.33, this was not a clinically significant value. Therefore, the overall
the degree of sedation from melatonin, as assessed by RASS, appeared to be negligible
compared to placebo.
The difference in RASS scores between the three time intervals (0-30 minutes,
30-60 minutes, and 60-90 minutes) was found to have little difference between them, for
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both the melatonin and placebo trials (all less than 0.5). Again, this indicated that the
degree of sedation did not change significantly over the course of 90 minutes. For both
trials, the degree of sedation increased from 0-30 and from 30-60 minutes, but between
60-90 minutes there was no difference in sedation (melatonin trial) or sedation actually
got less (placebo trial). While the RASS score for the melatonin trial at all time intervals
suggested a greater level of sedation compared to placebo, this difference was very small
and was not clinically or statistically significant.
However, even through the average decrease in RASS score in the melatonin trial
was small compared to that of the placebo trial, there was nonetheless signs that
melatonin may have sedative properties that is beyond that of the placebo effect.
Statistically significant sedation levels, as shown by RASS, at 60 and 90 minutes for the
melatonin trial indicate this potential. At the 60 minute time interval, the average RASS
score for the melatonin trial was less than that for the placebo trial to a statistically, if not
clinically, significant level. Together with the extent of VAS reduction, the RASS score
results gave some insight into the potential of melatonin to be used as an anxiolytic or
sedative premedication for anxious patients.
In order to determine the degree of cognitive impairment that may result from
exogenous administration of melatonin, a DSST was used. The greater the degree of
cognitive impairment, the lower the DSST score would be. The DSST score from the test
completed prior to drug administration (baseline value) was compared to the DSST score
from the test completed at 90 minutes after drug administration. The difference in these
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scores would indicate the extent of cognitive impairment: the greater than difference, the
greater the impairment. The results showed that the difference in DSST score from
baseline between melatonin and placebo trials was only -0.667 (negative value meant that
the melatonin trial yielded higher scores than the placebo trial). This was a very small
difference (less than 1). Therefore, it seems that at the doses used in this study, melatonin
did not impair the subject’s cognitive abilities beyond what is normal at 90 minutes after
its administration. This is a favourable finding, as it seemed to indicate that using
melatonin does not significantly affect cognitive function and therefore it is safe to use in
this respect.
The degree of psychomotor impairment from the administration of melatonin
compared to placebo was also assessed in this study. This was done by using the TDT.
Three aspects of TDT were assessed: number of dots missed, magnitude of the deviation
of the lines, and time required to complete the test. The greater the degree of
psychomotor impairment, the more dots will be missed, the greater will be the deviation
of lines, and longer time will be needed to complete the test. The baseline values obtained
prior to administration of drugs was compared to the values obtained 90 minutes after
drug administration. The results of the TDT were compared between the melatonin and
placebo trials, and the results showed that the difference between melatonin and placebo
trials for dots missed, line deviations, and time to complete test was only -0.083 dots,
5.83 mm, and 2.43 seconds (negative value meant that the melatonin trial yielded better
results than the placebo trial). For dots missed, the difference was too small to be of
clinical significance. For line deviations and time to complete the test, the differences did
86
seem to indicate that melatonin may impair psychomotor function to a certain degree
compared to placebo. However, statistical analysis showed that there were no significant
statistical difference between melatonin and placebo at any of the three aspects of the
TDT examined. Therefore, it appeared that the use of melatonin at the doses given did
not significantly affect the subject’s psychomotor skills compared to placebo after 90
minutes. Again, this finding further indicated the safety of melatonin, as it did not
appeared to significantly affect psychomotor function.
The 24-hour Quality of Recovery Questionnaire (QoR) was complete by each
subject over the telephone 24 hours after both the melatonin and placebo trials were
completed. The results showed that there was no significant difference with any of the
five questions from the QoR compared to placebo. It is understood and accepted that the
nature of postoperative recovery is heavily influenced by the anesthetic regimen, and so
the effect of melatonin on recovery is difficult to assess without controlling for the type
of anesthetic that the patient received, including the type of medications given, the doses
of the medications received, the length of anesthesia, and the type of dental procedures
done. Thus, even though there was no significant difference in recovery between
melatonin and placebo, it cannot be firmly concluded that melatonin does not adversely
affect recovery after general anesthesia. However, the QoR results do give some insight
into the quality of recovery and it does seem to suggest that the use of melatonin at the
given doses in patients undergoing general anesthesia may be acceptable in terms of
postoperative recovery, as it does not appear to have any negative impact on patient
recovery from anesthesia. The finding that melatonin did not significantly differ from
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placebo in terms of postoperative recovery further showed that adding melatonin to the
anesthetic regimen may be acceptable in terms of postoperative recovery. The question
that received the highest average score with melatonin was question 3 (average score of
5.00), which asked about dizziness, nausea, and vomiting. The lowest average score was
question 2 (average score of 4.42), which asked about the degree of confusion and ability
to understand instructions. This seemed to indicate that melatonin did not negatively
affect the degree of nausea and vomiting, which is one of the most undesirable outcomes
for patients who undergo anesthesia. The impaired ability to understand instructions may
be due to the sedative effect of melatonin, but considering the short half-live of melatonin
this seemed unlikely. This was likely due to the medications used for general anesthesia
more so than the effects of the melatonin premedication. The highest average score
received for placebo was question 3 (average score of 4.75), and the lowest score was
questions 1 and 2 (average score of 4.17). These findings were similar to that of
melatonin. This further supports the finding that melatonin did not have a negative effect
on these parameters, as its results were similar to that of placebo.
All aspects of this study which attempted to determine if melatonin administration
could have an affect on subject anxiety, sedation, cognitive ability, psychomotor ability,
and quality of recovery from general anesthesia showed that melatonin was no different
from placebo in its effects in all of these areas. There are several possible reasons why.
Perhaps melatonin cannot induce hypnosis/sedation at a high enough level in anxious
dental patients to be worthwhile in being used as an oral premedication. In other words, it
is not able to reduce anxiety to a low enough level in dental patients. Another reason is
88
that maybe the doses of melatonin were not large enough. The amount of melatonin used
in this study was between 7.5 to 15 mg, and this may not have been an adequate dose.
Perhaps a larger dose of melatonin was needed to induce adequate anxiolysis and
sedation. The RASS score differences between melatonin and placebo were very
minimal, indicating that the sedative effect of melatonin was not significant. This finding
further suggests that the dosage of melatonin used may not have been sufficient. The
subjects used in this study were highly anxious patients who required general anesthesia
for dental treatment. Perhaps melatonin may have been more effective in mild to
moderately anxious patients who require some sedation to receive dental treatment in a
conventional manner. Thus, melatonin may be an effective premedication if used in the
right population and situation.
Furthermore, certain conditions related to the production on endogenous
melatonin may have impacted the results of the study. Because melatonin levels in the
brain tend to fluctuate with the time of day, the time in which the trials were conducted
(morning or afternoon) may have had an impact on the study due to difference in
endogenous melatonin levels during those times of the day. Also, because the intake of
foods may affect melatonin production (the greater the intake of food, the more the
production of melatonin), subjects who had the trials done in the morning would have
been fasting (as per protocol for patients undergoing general anesthesia) for a shorter
period of time than subjects whose trials were done in the afternoon. This may have
affected endogenous melatonin levels because the longer the fasting period, the less
melatonin may have been produced. Subjects who were taking SSRI (selective serotonin
89
reuptake inhibitor) medications may have less melatonin production, since serotonin is a
precursor of melatonin and if serotonin reuptake is inhibited there is less of it available
for biosynthesis into melatonin. This could have had an impact on the results of the study.
With increasing age, the pineal gland tends to accumulate fluoride ions, which impairs its
ability to make melatonin. Therefore, subjects who were more advanced in age may have
lower levels of melatonin, and so these subjects may have responded differently to
exogenous melatonin than the younger subjects. Because melatonin production is
affected by light, the intensity of light exposure and duration of exposure on the subjects
during the trials could have affected their response to exogenous melatonin.
In terms of the DSST and TDT used in this study to examine cognitive and
psychomotor impairment, there was speculation that subjects may have done better on
these tests during the second trial as compared to the first trial, regardless of whether the
premedication was melatonin or placebo. This may be due to the learning effect, where
after subjects have completed a particular test, they perform better on that same test the
next time around simply due to the increased level of familiarity with that test. Statistical
analysis showed that for the DSST, the improvement in scores of the baseline test and the
end test in the second trial as compared to the first trial was statistically significant. The
TDT results showed that only on one of the three aspects of the test (line deviations) the
subjects on average did reasonably better at the second trial than the first, but none of the
comparisons from the three aspects of the TDT was statistically significant. Thus, for the
TDT, the effect that learning had on the test results was likely negligible. The learning
effect may have had more of an impact on the DSST results. However, because the end
90
test scores are examined relative to the baseline test score for both DSST and TDT, this
likely minimized the effect of learning on the overall results because it can be assumed
that both the end test score and baseline test score during the two trials (melatonin and
placebo) were equally affected. So it was likely that the learning affect (if present)
impacted both the melatonin and placebo trials in a similar manner, such that when the
results of the two trials are compared the impact of the learning effect was believed to be
negligible. Nonetheless, the learning effect cannot be completely ignored, and it is
acknowledged that this may have impacted the results of the TDT and DSST to a certain
extent.
It should be mentioned that although melatonin did not show a significant
difference in anxiety reduction relative to placebo, melatonin by itself decreased anxiety
to a significant extent during the 90 minutes as seen by the VAS score reduction of 21
mm relative to baseline, or a 33% reduction. This result does give some insight into the
potential of melatonin being used for premedication. If a control group that received no
premedication (no melatonin or placebo) was used and compared to melatonin, it could
be inferred that the anxiety level of these subjects would have likely increased over time
or remained consistently high. In this sense, melatonin may still prove to be useful in
alleviating patient anxiety.
This finding is especially worth noting due to the currently understanding of the
placebo effect. Traditionally, the placebo that is used to study drugs has been considered
to have little or no efficacy and that the real drug to which it was being compared to had
91
to be superior relative to placebo in order for it to be considered effective in its
therapeutic effect (Greene et al., 2009). This is because placebo was believed to represent
a psychological phenomenon and not considered to be biologically real. However, as
reported by Greene et al. (2009), placebos do in fact elicit biological and behavioural
responses in humans. Therefore, the use of a placebo itself can be considered therapeutic
and an effective method of treatment. In this sense, the effect of melatonin by itself,
which resulted in a significant decrease in patient anxiety and sedation, can be viewed as
an agent having a significant effect on the patients. In this study, the placebo effect was
found to be quite significant, as shown by the level of anxiolysis and sedation that
resulted from the placebo trials. This further showed that placebo is a real entity, and not
an imaginary construct. Just because the effects of melatonin were no different from that
of placebo does not mean that it is not effective, because placebo itself can be regarded as
a method of treatment on its own. Had the subjects not received any premedication
(melatonin nor placebo), it is not unreasonable to deduce that the level of anxiety would
have increased or been maintained at a high level. Therefore, the results of this study did
not rule out melatonin’s potential to be used as an oral premedication, despite showing no
significant difference from placebo.
Conclusion In this study, melatonin was used at doses of 7.5 mg, 10 mg, 12.5 mg, and 15 mg
on a sliding scale to determine if its anxiolytic and sedative properties are effective
enough to be used to alleviate anxiety in anxious patients undergoing general anesthesia
for dental treatment. The degree of cognitive and psychomotor impairment from the
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administration of melatonin was also measured, as well as the quality of recovery from
the general anesthetic with melatonin as a premedication.
Based on the findings of this study, compared to placebo, melatonin at the doses
used did not significantly reduce the patient’s level of anxiety or sedation. There were no
significant cognitive or psychomotor impairments from its administration, and the quality
of recovery was not significantly different from that found with placebo. The patient’s
heart rate and blood pressure, which is expected to change with different degrees of
anxiety, also showed no significant differences.
Therefore, the null hypothesis (Ho) for this study was accepted: that the
hypnotic/sedative effects of melatonin, when used as premedication in adult patients
undergoing dental treatment under general anesthesia, is no different from placebo in
alleviating their anxiety.
Future Directions In order to further explore the potential for melatonin to be used for
premedication in the field of dentistry, additional investigations are needed. These should
include dose-response studies where different doses of melatonin are used and compared
to placebo, to take into account the possibility that the doses used in this study may not
have been sufficient to elicit its anxiolytic and sedative effects. It may be possible that
there exists a certain dose that would results in effective anxiolysis and sedation without
cognitive or psychomotor impairment.
93
A study comparing melatonin with benzodiazepines, the current gold standard in
dental premedication, would be another worthwhile study to conduct. This would help to
examine the effectiveness of melatonin against benzodiazepines and also to compare the
severity of side effects between them. This way, it would be more clear as to whether
melatonin could be used as effectively as benzodiazepines and if the severity of side
effects is less for melatonin, thus making it a preferred agent.
Finally, a study of melatonin premedication using patients who are to undergo
conventional dental treatment, rather than dental treatment under general anesthesia,
would be of value. In the current study, melatonin was used as premedication not for
dental treatment per se, but for induction of general anesthesia. Anxiety regarding the
dental procedure itself may differ from that of receiving a general anesthetic, and perhaps
melatonin may be more effective in this context. Thus, examining anxious patients who
are to undergo conventional dental treatment would shed more light into the usefulness of
melatonin as a premedication in the field of dentistry.
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Dollins, AB, Lynch, HJ, Wurtman, RJ, Deng, MH, Kischka, KU, Gleason, RE, Lieberman, HR. Effect of pharmacological daytime doses of melatonin on human mood and performance. Psychopharmacology 1993;112(4):490-496.
Donaldson M, Gizzarelli G, Chanpong B. Oral Sedation: A Primer on Anxiolysis for the Adult Patient. Anesthesia Progress 54: 118-129, 2007
Douglass C, de Vries J, Joshipura K, Kakar A, Lopez N, Mann J. Oral and systemic health consensus statement from an international panel. Inside Dentistry 2006;2(1):1-12 Economou G. Dental Anxiety and Personality: Investigating the Relationship Between Dental Anxiety and Self-Consciousness. Journal of Dental Education 2003; Vol 67, No 9, 970-980 Fauteck J, Schmidt H, Lerchl A, Kurlemann G, Wittkowski W. Melatoninin epilepsy: first results of replacement therapy and first clinical results. Biological Signals and Receptors 1999;8(1-2):105-110 Fragen RJ, Caldwell NC. Lorazepam Premedication: Lack of Recall and Relief of Anxiety. Anesthesia and Analgesia Vol 55, No 6, Nov-Dec 1976, 792-796 Greene CS, Goddard G, Macaluso GM, Mauro G. Topical Review: Placebo Responses and Therapeutic Responses. How Are They Related? Journal of Orofacial Pain Vol 23, No 2, 2009: 93-108 Guynup S., editor. Oral and Whole Body Health. Scientific American New York: Scientific American, Inc., 2006
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Isik B, Baygin O, Bodur H. Premedication with melatonin vs midazolam in anxious children. Pediatric Anesthesia 2008 18: 635-641 Johnson K, Page A, Williams H, Wassemer E, Whitehouse W. The Use of Melatonin as an Alternative to Sedation in Uncooperative Children Undergoing an MRI Examination. Clinical Radiology (2002) 57: 502-506 Kindler CH, Harms C, Amsler F, Ihde-Scholl T, Scheidegger D. The Visual Analog Scale Allows Effective Preoperative Anxiety and Detection of Patients’ Anaesthetic Concerns. Anesthesia and Analgesia 2000;90: 706-12 Hardeland R, Pandi-Perumal SR, Cardinali DP. Melatonin. The International Journal of Biochemistry & Cell Biology 38 (2006): 313-316 Hindmarch I. Psychomotor Function and Psychoactive Drugs. British Journal of Clinical Pharmacology 1980; 10: 189-209 Ismail SA, Mowafi HA. Melatonin Provides Anxiolysis, Enhances Analgesia, Decreases Intraocular Pressure, and Promotes Better Operating Conditions During Cataract Surgery Under Topical Anesthesia. Anesthesia and Analgesia 2009;108: 1146-51 Lamberg, L. Melatonin potentially useful but safety, efficacy remain uncertain. Journal of the American Medical Association 10-2-1996;276(13):1011-1014 Lu DP, Lu WI. Practical Oral Sedation In Dentistry: Part II – Clinical Application of Various Oral Sedative and Discussion. Compendium September 2006; 27(9) 500-508 Melatonin Monograph. Alternative Medicine Review Dec 2005, Vol 10, No 4, 326-336 Merchant AT. Losing teeth leads to an unhealthy diet associated with cardiovascular disease risk. Journal of Evidence Based Dental Practice 2006;6(2):187-188 Myles PS, Hunt JO, Nightingale CE, Fletcher H, Beh T, Tanil D, Nagy A, Rubinstein A, Ponsford J. Development and Psychometric Testing of a Quality of Recovery Score After General Anesthesia and Surgery in Adults. Anesthesia and Analgesia 1999; 88: 83-90 Naguib M, Samarkandi, AH. Premedication with melatonin: a double-blind, placebo-controlled comparison with midazolam. British Journal of Anaesthesia 1999; 82 (6): 875-880 Naguib M, Samarkandi, AH. The Comparative Dose-Response Effects of Melatonin and Midazolam for Premedication of Adult Patients: A Double-Blinded, Placebo-Controlled Study. Anesthesia and Analgesia, 2000; 91: 473-479
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Naguib M, Gottumukkala V, Goldstein PA. Melatonin and Anesthesia: a clinical perspective. Journal of Pineal Research 2007; 42: 12-21 Nava F, Carta G. Melatonin reduces anxiety induced by lipopolysaccaride in the rat. Neuroscicence Letters 307(1): 57-60, 2001 Jul 6 Raat H, Bonsel GJ, Hoogeveen WC, Essink-Bot ML. Feasibility and Reliability of a Mailed Questionnaire to Obtain Visual Analogue Scale Valuations for Health States Defined by the Health Utilities Index Mark 3. Medical Care 2004; 42: 13-18 Samarkandi A., Naguib M., Riad W, Thalaj A, Alotibi W, Aldammas F, Albassam A. Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study. European Journal of Anaesthesiology 2005; 22: 189-196 Schmidt C-M, Knief A, Deuster D, Matulat P, Zehnhoff-Dinnesen AG. Melatonin is a Useful Alternative to Sedation in Children Undergoing Brainstem Audiometry with an Age Dependent Success Rate – A Field Report of 250 Investigations. Neuropediatrics 2007; 38: 2-4 Sessler CN, Gosnell MS, Grap MJ, Brophy GM, O’Neal PV, Keane KA, Tesoro EP, Elswick RK. The Richmond Agitation-Sedation Scale. American Journal of Respiratory and Critical Care Medicine 2002; 166: 1338-1344 Sheldon, SH. Pro-convulsant effects of oral melatonin in neurologically disabled children. Lancet 1998;351(9111):1254 Sherman SA, Eisen S, Burwinkle TM, Varni JW. The PedsQL Present Functioning Visual Analogue Scales: preliminary reliability and validity. Health and Quality of Life Outcomes 2006, 4:75 Siddiqui MA, Nazmi AS, Karim S, Khan R, Pillai KK, Pal SN. Effect of melatonin and valproate in epilepsy and depression. Indian Journal of Pharmacology 2001;33:378-381 Suhner A, Schlagenhauf P, Johnson R, Tschopp A, and Steffen R. Comparative study to determine the optimal melatonin dosage form for the alleviation of jet lag. Chronobiology International 1998;15(6):655-665. Sury MRJ, Fairweather K. The effect of melatonin on sedation of children undergoing magnetic resonance imaging. British Journal of Anaesthesia 98(2): 220-225 (2006) Tamiya N, Araki S, Ohi G, Inagaki K, Urano N, Hirano W, Daltroy LH. Assessment of pain, depression, and anxiety by visual analogue scale in Japanese women with rheumatoid arthritis. Scandinavian Journal of Caring Science 2002; 16: 137-141 Trieger N, Newman MG, Miller JC. Measuring Recovery From Anesthesia – A Simple Test. Anesthesia and Analgesia 1969; 48 (1): 136-140
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APPENDIX
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Appendix 1
Inclusion and Exclusion Criteria Checklist Inclusion Criteria Yes No
(1) In good health (ASA I or II) _____ _____
(2) Not taking benzodiazepines or barbiturates _____ _____
(3) Ages 18-70 years _____ _____
(4) Body weight between 40-120 kg _____ _____
(5) Baseline VAS anxiety score of at least 40 mm _____ _____
(6) No seizure disorders _____ _____
(7) Not taking anticoagulant medication _____ _____
(8) Needing at least two appointments _____ _____
(9) Informed consent signed _____ _____
Exclusion Criteria
(1) ASA III or higher _____ _____
(2) Taking benzodiazepines or barbiturates _____ _____
(3) Age less than 18 years or over 70 years _____ _____
(4) Body weight less than 40 kg or over 120 kg _____ _____
(5) Pregnancy _____ _____
(6) Baseline VAS anxiety score of less than 40 mm _____ _____
(7) Has seizure disorder _____ _____
(8) Taking anticoagulant medication _____ _____
(9) Needing less than two appointments _____ _____
(10) Inform consent not signed _____ _____
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Appendix 2
Consent Form
I _________________________ have listened to Dr. Daniel Lee’s explanation about
the purpose of the study and what it entails. I have had an opportunity to discuss any
concerns or questions that I may have. I am satisfied with the explanation that I have
been given, and I understand what I must do to complete my participation in this study. I
understand the possible complications in participating in this study involving melatonin,
which includes disorientation, fatigue, headaches, dizziness, and vivid
dreams/nightmares.
I understand and am willing to accept the risks to participate in this study. I understand
that I am not obligated to complete the study once it begins and that my participation is
voluntary and that I may withdraw at any time.
Any information that is acquired about myself during this study will be confidential
and neither my name nor any other identifying information will be made available to
anyone other than the investigators, nor will such information appear in any publications.
I have read and understood the attached information sheet. I have had an opportunity to
ask any questions I may have had, and my questions have been answered to my
satisfaction.
_________________________ __________________________ Date Date _________________________ ___________________________ Signature of Subject Signature of Witness _________________________ ___________________________ Print Name Print Name
100
Appendix 3
Information Sheet
Title of Study:
A Study of Melatonin for Premedication Prior to Anesthesia
You have expressed an interest in participating in this study that is designed to
evaluate the ability of melatonin to reduce anxiety prior to start of anesthesia for dental
treatment. It is a study being carried out at the Faculty of Dentistry, University of
Toronto. If you choose to participate, you will be required to attend at least two
appointments in the Graduate Anesthesia Clinic at the Faculty of Dentistry, University of
Toronto. At the first appointment, you will receive either the melatonin or a non-drug
substance that looks, feels, and tastes like melatonin but without any pharmacological
properties. At your second appointment, you will receive whichever substance that you
did not receive at your first appointment. You will not know which one you received at
either appointments. At both appointments, you will be shown how to use a visual analog
scale (VAS) to draw a line to represent the amount of anxiety that you are feeling before
taking the drug. At 30, 60 and 90 minutes after taking the drug, you will be asked to
repeat the VAS at each time interval. You will also be asked to complete two separate
questionnaires, once before taking the drug, and once more before commencing treatment
under anesthesia. These questionnaires will examine your level of alertness and ability to
function after taking the study drug. Also at each time interval, your level of sedation will
be assessed by the researcher. After 90 minutes from the time you took the drug, you will
be seen by the anesthesia resident to have dental treatment done under anesthesia. Dr. Lee
will be contacting you by phone twenty-four hours after your anesthesia appointment to
ask a few questions. You are reminded that your participation in this study is voluntary
and that you may withdraw at any time. A gratuity of $50.00 will be paid to each
participant who completes all aspects of the study.