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Introduction
Dentistry is one of the most important technological advances in human history.
There would be unbearable suffering and people may die younger from a loss of appetite
associated with the pain they have in their mouths without it. People had to endure
long, painful tooth surgery in the beginning, without any known ways to alleviate the
stress. New methods of pain control developed over time, with a key component being
the introduction of local anesthesia. From its long history starting in the late 19th
century, local anesthesia has evolved in many ways from the highly allergenic Novocain
to the much less harmful Articaine (Snoeck, 2012). Unfortunately, there are many
factors that affect anesthesia’s effectiveness. In many cases the patient receiving it must
have a good state of mental health and must be willing to cooperate with the dentist if
directions are understood. The age of a patient, and even physical health can greatly
affect how well anesthesia works, and for how long. The technique the dentist uses for
delivery of local anesthesia also plays an important role. Improper delivery or having
the needle cut into neurons by chance can have a prolonged numbing effect on patients
for additional weeks after a surgery finishes (Smith and Lung, 2006). This paper will
review: some of the history of dentistry, the development of modern anesthesia, the
dangers associated with current anesthetic delivery practice, and new techniques
currently being developed that may be suitable replacements for needle-based delivery.
A Brief Introduction of Dental Surgery
Dentistry has been a part of human history since a couple thousand years BCE.
Many concerns arose from pain caused in the dental pulp and dentin layers of the teeth.

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In a review of dental history by Forrai (2009) many of the common problems faced in the
past were addressed. The unexplained pains were thought to have come from
mysterious “tooth worms”, as the evidence was the nerve tissues that erupted from deeply
infected carious teeth. As knowledge of oral care was not well known thousands of
years ago, it is understandable that our ancestors thought in such a primitive way.
Ancient Egypt began writing about dental and oral health care approximately between
1700-1500 BCE in a guide called the Papyrus Ebers (usually referred to as the Ebers).
The dentists of ancient Egypt worked mainly in the royal courts of the pharaoh and the
treatment provided would only be available to those with access to the courts. This
practice led to only the higher-class members of society benefiting from any knowledge
of oral health care that existed during this time. Even then, the dental groups within the
courts were divided into two categories known as the “dentists” and the “great dentists”.
These dentists were also limited in the amount of treatment options available for patients
at the time because they all most likely followed the Ebers. All work prior to the
official printing of the Ebers is comparable to modern day research with test subjects and
experimenting with different types of treatments to see which would work best for each
type of situation.
Within the Ebers various treatment methods were recorded regarding tooth ache,
surgical removal, and infections. It contains a very early list of ingredients that were
used for the first dental fillings that was made from clay and lotion. The Ebers also had
a remedy for halitosis that involved the use of strongly scented spices boiled with honey
and molded into what could be considered the prototype of pills. A gold wire was used
to wrap loose teeth together with more stable neighboring teeth to create early forms of

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dental bridges, which is seen in Figure 1. If the teeth were found to be too loose, the
dentists would remove them from the patient’s mouth by hand. Other forms of care
included drilling directly into the jawbone to drain abscesses, and the use of spices like
myrrh to fight gingival infections, as seen in Figure 2.
Figure 1. One of the oldest bridges discovered in Egypt (Forrai, 2009).
Figure 2. Jawbone drilled for the draining of an abscess (Forrai, 2009).
Since knowledge of oral health care was extremely poor at the time the Ebers
were written, many holistic forms of care were used. Like dentists today the ancient
Egyptian dentists focused on helping their patients prevent dental health issues far more

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than they worked on already damaged mouths. It has even been listed in the Ebers that
patients with multi-fractured jaws should be avoided since any attempt to fix the issue
will often result in serious infections that lead to death soon after. The ingredients used
in most of their remedies had antibacterial properties that made them quite ideal for a
variety of treatments, especially in antiseptic therapy.
What is Anesthesia?
A review by Snoeck (2012) reveals a brief history of anesthesia, and the most
commonly used form in dentistry currently. In 1886 cocaine was the first developed
anesthesia successfully used in surgeries. It was a revolutionary discovery during the time
period and little was known about the negative side effects that would ensue. A few
years after it began use heavily people began to realize that the ester based anesthesia was
actually causing allergic reactions in many patients during post-surgery recovery. In an
attempt to find a replacement for it, lignocaine was synthesized by the Swedish chemist
Nils Löfgren in 1943 using an amide structure to replace the ester, and it was later
introduced into the public under the generic name lidocaine (Snoeck, 2012). This
proved to be successful as a replacement for cocaine as anesthesia. Since then multiple
forms of anesthesia have been created to allow for variations in treatments based on the
patients’ immune responses to each particular drug.
Articaine is one of the most used forms of anesthesia in dentistry currently. As
seen in Figure 3, articaine is different in chemical structure from other forms of
commonly used anesthesia because it contains a thiophene ring while the others contain
some form of benzene ring. Articaine also has an ester group attached to its ring

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structure, which allows for it to be rapidly metabolized in a nonspecific manner by all
cells, and can be excreted easily from the body. The other benefit of having the ester
group allows for easier diffusion across cellular membranes.
Figure 3. Various structures of anesthesia in dentistry provided using a comparison of the
chemical structures of prilocaine, procaine, articaine, and tetracaine, alternative forms of
anesthesia used in dentistry (Snoeck, 2012).
Anesthesia works by temporarily binding to the alpha-subunits of voltage-gated
sodium channels found within neurons. This works as a plug that prevents the influx of
sodium across the dendrites even in the presence of an excitatory stimulus, which then
prevents an action potential from being reached. These forms of anesthesia are also
state dependent when considering the activity of the sodium-gated channels. Anesthesia
binds the most easily to neurons amidst the creation of action potentials when their
channels are opened, and binds the least when neurons are not attempting to send out
signals. This is important because it allows for very specific binding to target cells,

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while it allows the functionality of other cells to remain unaffected. It also has a higher
potency when binding to neurons with a smaller diameter axon that has been myelinated.
The average time it takes for the efficacy of the drug directly depends on the number of
voltage-gated channel proteins within a neuron. Anesthesia also has a vasodilatory
effect causing an increased volume of transportation within the veins unless it is
combatted with a vasoconstrictor such as epinephrine.
Articaine is rapidly hydrolyzed by cholinesterase found in blood plasma and
becomes its inactive form of articainic acid. This allows for the drug to be safely
transported throughout the body without risk of it damaging vital organs such as the
heart. It has been found that the average half-life of articaine is 60 minutes. This
means the majority of the anesthesia should be excreted from the body within the first 3
hours immediately following the application of the drug. Patients with renal problems
also need to take special care when given anesthesia since their liver sometimes cannot
properly filter out articaine and articainic acid. This condition often leads to what is
known as Local Anesthetic Systemic Toxicity, or LAST. Children are also at much
higher risk of forming such conditions since their blood plasma does not have as many
proteins to allow for binding of anesthesia. Studies have also shown that articaine
degradation is independent of age as long as the patient it is administered to is considered
a healthy for their age group (Snoeck, 2012).
Effectiveness of Transcutaneous Electrical Nerve Stimulation
It is important to address the problem of pain associated with dentistry. This is
especially vital for children and adults experiencing their first visit to the dental office.

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Typically, parents are encouraged to bring their children to dental offices as soon as two
years old to have them become exposed to dental equipment as early as possible and
make them comfortable while in the office. Of course, this is simply an added benefit to
ensuring the child's teeth grow properly and in a healthy manner. The main trouble
children and adults experience when they visit a dental office is the initial fear of having
an anesthetic injection applied to their gingiva. The pain they experience is often
described as the most painful and influential in their visit to the dental office, which often
influences their behavior in most future visits.
A study from Varadharaja, Udhya, Srinivasan, Sivakumar, Karthik, and
Manivanan (2014) observed the amount of pain associated with dental visits and that
strictly affected by the initial anesthesia injection by needle. In the study, dentists used
two types of materials for pain management: Transcutaneous Electrical Nerve Stimulator
(TENS), and the traditional injection method of local anesthesia. These forms of pain
management were used prior to various procedures performed requiring a dental dam.
All pain was measured using a self-reported visual analog scale, detailed in Figure 4,
compared to heart rate of the patient. There was a total of 62 patients who ranged from
ages 6 to 12, who also never previously were aware of TENS procedures, but the
procedure was explained prior to application. It was found that patients subject to
TENS had significantly less pain than those subject to invasive anesthesia applied by
needle injection.

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Figure 4. The Modified child dental anxiety scale (Varadharaja et al., 2014).
In the review written by DeSantana, Walsh, Vance, Rakel, and Sluka (2014),
TENS is commented on its effectiveness of pain management. TENS is a noninvasive
form of pain treatment that works by providing an electrical stimulus through the use of
electrodes attached to the periphery of the pain afflicted area. The electric current
provided ranges from low to high frequency to stimulate the two different types of
neurons (sensory and motor). The low frequency electric currents stimulate the motor

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neurons while the high frequency often stimulates the sensory neurons. The stimulation
provided turns on various opioid receptors found in the spinal cord and the brainstem.
This is important because these locations in the body are principally responsible for the
pain signal transduction. By activating these receptors an opioid-like response is
invoked and the cells receiving this stimuli become desensitized to other forms of
stimulus until the electric current is removed. Studies performed on lab rats helped
conclude that TENS is useful in prevention of pain rather than removing an already
established pain in the body. The pain relief provided by TENS is unusual because it is
not affected by other topical analgesics applied to the same area, but the effectiveness is
greatly diminished if an invasive form of anesthesia is applied to the same area. It is
also unusual because TENS works on the contralateral, or opposite, limb where the pain
is being expressed prior to inflammation build-up, but it works just as effective on either
limb when applied after inflammation has occurred.
A Study of Anxiety and Pre-Anesthetic Analgesia
Another study was performed by Kapur, Chawla, Gauba, Goyal, and Bhardwaj
(2014) to test the effects of the topical sedative midazolam in anxiety management of
children up to and including the age of 4. In their study they had a sample of 40 patients
with a split among them to have half receive the treatment with midazolam prior to local
anesthetic injection, while the other half would receive the placebo treatment prior to
injection. All the patients in this study were getting an amalgam filling for one molar
tooth on the mandibular jaw and had never had prior experience in a dental office.
Either the midazolam or placebo were mixed with strawberry jelly and were given to the

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children 15 minutes before the procedure was to begin. The children were also given
the jelly mixture in a separate room away from the dental instruments and sounds so as to
not frighten them. The dentist would then take the children to the operatory chair
accompanied by his/her parents/guardians and the procedure would begin.
Kapur et al. (2014) found that initially children had been a significant change in
the amount of anxiety experienced prior to their entry to the dental operation room who
were treated with midazolam, shown in Table 1. For all steps afterwards, however, the
children who were subject to midazolam had reduction in the anxiety they experienced,
with significant reduction during the application of a local anesthetic. The group of
children that had received the placebo had no significant reduction of anxiety in any of
the steps leading up to the operation. It was even found that the children who just
received the placebo had increased their anxiety levels when it was time for them to go to
the dental chair. All values of anxiety were measured using the Venham’s Clinical
Anxiety Rating Scale, seen in Table 2. In all cases using the midazolam children were
compliant with the requests and procedures of the dentist during every stage of the
operation, while in most cases using the placebo treatment the children were often very
reluctant to follow the requests of the dentist and made treatment somewhat difficult.
This is also supported by the evidence that far fewer children were unable to finish
treatment due to anxiety when they were given midazolam than children who did not
receive it.

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Table 1. A Comparison of the anxiety levels in children up to age 4 with sedation drug
pre-treatment vs. placebo effectiveness (Kapur et al., 2014).
Table 2. Venham’s Clinical Anxiety Rating Scale (Kapur et al., 2014).

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Overall, it can be concluded that people of all ages experience fear at the dental
office. That fear stems from anticipation of pain and suffering, and the new sights of
drills with loud noises is particularly traumatizing for children who have never been to
the dentist before. Typically, dentists have to use a form of sedation to make children be
cooperative for operations. Many options available to dentists also have strong negative
side effects that could make the experience worse for children the next time they make a
visit. Midazolam is a great tool that is very effective in reducing stress experienced in
the dental office, and it is something that should be strongly considered even for patients
who are above the age group in this study.
Practical Applications of Local Anesthesia
Peedikayil and Vijavan (2013) had studied the effects of anesthesia in their
pediatric patients with the intention of reviewing current methods of anesthesia
administration to young patients. They explained that currently there are two different
types of anesthesia injections, which are amide based and ester based, with the most
common type of anesthesia used in children being the amide based. The most used of
these local anesthetics is lidocaine hydrochloride (2%) because it has the least allergenic
properties of all currently available local anesthesia. It was also noted that many forms
of local anesthetics will also contain some form of vasoconstrictor to allow for a
reduction in the chances of blood toxicity, while it also allows for reduced blood flow to
the area of injection for what is considered a “bloodless” surgery. It is recommended
that all infections be absent when providing a local anesthetic injection because the
infected area has a high risk of reducing the onset of the anesthesia, and can possibly

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prevent it completely from working. An infection causes the area of inflammation to
have an upset pH balance from the normal value of 7.4 to a much more acidic value of
5.6, which will then make it difficult for the anesthesia to bind to the voltage-gated
channels in neurons because the forms of anesthesia have bases that can easily bind to the
free-floating acids. Injections into an infected area are also able to cause the infection to
spread to any other area in the mouth the needle touches after.
Local anesthetics are commonly used because there is very little risk associated
with their use, while the side effects that can occur are usually not life-threatening, as
seen in Table 3. The highest chance of producing an adverse effect in children is by
accidental overdose of anesthesia. This is fairly common because children often vary
greatly in size and weight which makes it quite difficult to gauge the dosage that is being
applied to each child. Toxicity from overdose can lead to either stimulation or
depression of the central nervous system. If stimulation occurs then patients can express
physical indicators such as sweating and hyperactivity. If depression occurs then
patients may experience bradycardia (an abnormally slow heart beat), hypoxia (oxygen
deficiency in tissues), or respiratory arrest (Peedikayil and Vijavan, 2013).

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Table 3. A List of common negative effects associated with local anesthesia usage
(Peedikayil and Vijavan, 2013).
The local anesthesia that has the highest rate of causing allergic reactions is
procaine whose main antigen is para-aminobenzoic acid, which is also known as PABA.
There are a number of allergic reactions that could occur including dermatitis and
photosensitivity, but the most dangerous is anaphylaxis. Patients who are aware of
allergies to anesthesia, but are unable to identify the exact allergen should be tested by an
allergy specialist before they proceed with the dental treatment. Patients allergic to
bisulfate will have injections without epinephrine, which can pose a much higher risk of
having the patient experience toxicity from a higher concentration of anesthesia entering
the bloodstream more easily.

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Administration of local anesthesia in pediatric patients poses some difficulty
especially when children tend not to cooperate with the dentist. It has been suggested
that a number of different pre-injection preparations can be used to increase the chances
of success. The first technique mentioned is the control of the child’s head and hands.
There is great fear that if a child grabs the syringe while the dentist is trying to inject the
anesthesia the child may accidentally have the needle poke into another area of the mouth
and cause a somewhat traumatic experience for all future visits to the dental office.
Therefore, it was recommended that dentists have their assistant gently, but firmly,
restrain the child’s hands and head during the injection. The second technique
mentioned is the use of topical anesthesia in preparation of a needle injection. The
topical anesthesia helps to numb the area it is applied to by lightly penetrating the cells it
is attached to remove some feeling directly from the area it was applied to. Topical
anesthesia should be applied to areas that have been dried out for maximum efficacy.
The third technique mentioned is to use shorter needle lengths since children have
smaller mouths compared to adults. The smaller needle size allows the dentist to have
better control over his/her hands. It has also been suggested that the injection should be
made slowly to prevent rapid systemic absorption and the patient should inhale before the
injection begins. If the anesthesia was not successful after the first injection, a second
injection is recommended soon after since the area of application has already been
penetrated by the needle, thus making it easier to maneuver the needle to the correct
position (Peedikayil and Vijavan, 2013).
Different forms of local anesthesia is performed depending on the location of the
tooth needing surgery. Maxillary teeth, explained in Figure 5, in need of surgery

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typically have the needle inserted into the buccal fold (the part of the cheek that touches
the teeth) and is slowly pushed toward the tooth roots where the anesthesia is applied.
This works particularly well in children because their bones are weaker which allows
needle penetration to occur more easily across bone tissue. The needle may be inserted
through the mucous membranes of the mouth near the target tooth and can be pushed
deeper slowly following the flow of respiration and releasing small increments of
anesthesia until the root has been reached. It is also interesting to note that the
maxillary bone is much more fragile than the mandible in nearly all animals because the
mandible uses muscle to move, especially in grinding food, while the maxilla simply
stays in place. Typically an anesthetic block is applied to the mandible, viewable in
Figure 5, instead of infiltration due to the increased thickness of the jaw. The advantage
to using an anesthetic block is that it allows the numbing of multiple areas within the
mouth which then gives the dentist the opportunity to work on multiple teeth within the
blocked area (Peedikayil and Vijavan, 2013).
Figure 5. Image of the human skull anatomy (Healthwise, 2014).

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A technique called the intraligamentary injection is used on periodontal, or gum,
ligaments. The needle is inserted into the mesiobuccal (middle, gum-oriented) part of
the root of the tooth the surgery is being performed on. A special type of syringe is used
for this type of injection and is lightly inserted into the gum-line instead of being pushed
into the bone like most other applications of anesthesia. The needle is also typically
inserted with the bevel pointed toward the bone even though this is more of a preference
than having an actual effect. Since this form of anesthesia does not affect the roots
directly, it has a more varied range of duration and is typically saved for use after the
initial application of anesthesia has failed. This method is saved for a type of last resort
because it has a very high risk of transferring bacteria to sensitive tissue and could more
easily cause the spread of an infection.
Another form of anesthesia is known as the intrapulpal technique, which works by
applying pressure to the root. This method has been proven to work even with the use
of a saline solution, although the exact reason has not been discussed. Intrapulpal
method can be used when a cavity has been made deep enough in the tooth that there is
access to the roots without using any type of instrument. The needle normally must
have a snug fit so that pressure may be easily applied and relieve the patient of pain.
When the cavity is too wide to apply pressure in this manner, the tooth is soaked in a
topical analgesic for approximately one minute, then the needle is forced into the dental
pulp as far as it can possibly reach and the anesthesia is applied in this area as pressure
can now be applied much more easily (Peedikayil and Vijavan, 2013).
In addition to the mentioned techniques, newer methods of successfully applying
local anesthesia are being developed and tested. One type of newer anesthesia

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administration is called the computerized local anesthesia. During its administration the
dentist uses a wand with needle attached to one end, and a cord connecting it to a
miniaturized computer from the other end. The dentist sets the pressure: volume ratio
before placing the needle into the gingiva. Once it is inserted the dentist pushes the start
button and the anesthesia is applied at the ratio specified by the computer. The system
takes into consideration all changes in resistance and ensures the constant ratio specified.
There are many problems associated with this technique as well when compared with
more traditional methods of providing local anesthesia. The more significant concerns
involving computerized local anesthesia are the cost of using it in a dental office, and the
slower time it takes to deliver anesthesia when compared to more traditional techniques.
The concept of using electrical stimulation in lieu of invasive needles is a fairly
recent concept that is showing promising results. The electronic dental anesthesia
method uses TENS to stimulate the nerves enough to cause a block in signal transduction
pathways between the neurons where the surgery is to be performed. While this
technique is useful in healthy patients, it is advised not to be used on patients suffering
from neurological disorders related to regions specific to the head and neck, patients with
heart, skin, and bleeding disorders. For those types of patients, an intraoral lidocaine
patch can be used instead. This patch applies a constant supply of lidocaine anesthesia
to the area it is applied to, and must be placed on the mucosal membrane inside the
mouth. This patch is used to remove pain sensitivity on the surface, making it less
painful for the injection of local anesthesia soon after. One of the newest techniques
created is the jet injection, which uses only highly pressurized pumps to attempt to force
anesthesia into the skin. Currently, it is known to be much less effective than traditional

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methods while it is also more expensive because of the need for a machine that can
produce the pressure necessary to use it (Peedikayil and Vijavan, 2013).
Epinephrine’s Role in Anesthesia
Epinephrine is known to cause vasodilation effects in the areas it is applied to
along with the administration of local anesthesia, but there are other side effects that
come along with its use during oral surgery. Annamalai, Chandrakala, Kumar, Prince,
Sivanmalai, and Thangaswamy (2012) were interested in the other effects that haven’t
been recorded by researchers in the past, so they launched an investigation to find the
answer. In their research, a group of 30 patients were studied who were receiving oral
surgery for the removal of their third molar teeth, known as the wisdom teeth. All the
patients were healthy who participated in the study and had no known cardiovascular
issues. The patients were provided with a general anesthesia intravenously starting
approximately 1 hour before their surgeries began, and they were given local anesthesia
in close proximity to the location of surgery. In this study, half the patients were
provided with 2% lignocaine using a 1: 200,000 ratio of adrenaline: lignocaine, while the
other half received 2% lignocaine with no other chemical compounds. A total of 5ml
blood was obtained from the patients to determine the blood glucose concentrations and
serum potassium concentrations after the anesthesia was injected. 5ml samples of blood
were collected: immediately after local anesthetic injection, 1 minute, 10 minutes, and 20
minutes after the injection, so sugar and blood potassium levels could be compared.
Annamalai et al. (2012) determined that they would use the time of blood
collection at 1 minute to be the baseline blood concentrations of each of the two groups

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studied, and would have the others used for comparison with each other. Group I was
indicated as the group that received only the 2% lignocaine, while group II was chosen as
the patients who would receive trace amounts of epinephrine in addition to the lignocaine
shots. Annamalai et al. (2012) had also decided that any P-values used in this study that
were less than 0.05 were significant changes in concentrations. Looking at Table 4, it is
possible to see that the patients in both groups had significant changes in blood glucose
levels, while the patients in group II experienced significant changes in serum potassium
levels only at time 0, while the patients in group I only experienced significant changes in
serum potassium levels at the 10 minute time frame.
Table 4. Probability of changes in blood glucose and blood potassium concentrations
after administration of local anesthesia measured at pre-determined time intervals
(Annamalai et al., 2012).
The results from this study were similar to results from others in the past. In
other studies there was a higher concentration of potassium, known as hyperkalemia,
upon injection of the epinephrine prior to surgery, but there was a much lower

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concentration, called hypokalemia, once the anesthesia had time to pass through the
blood. It has also been noted that hypokalemia is a common reaction in patients after
receiving local anesthetic injections. In this study, however, there had not been a
hyperkalemic effect indicating that the speed of injection may play an important role in
its detection, especially since hyperkalemia is dose-dependent and the times chosen to
observe blood concentrations may have been during inopportune times to see these
effects. The change in blood glucose levels indicate that epinephrine does have some
importance in the body’s ability to regulate sugar levels. In particular, the blood glucose
levels of the patients in this study had increased by significant concentrations for the
majority of the time after receiving the injections containing epinephrine. This may be
related to the vasodilation effects of epinephrine especially in the renal system employed
by the kidneys which regulates the blood osmolarity content. There were no significant
changes in the heart rate for either of the groups studied as well; indicating that heart rate
is independent of chemicals involved in lignocaine and epinephrine. It appears that
overall the use of epinephrine in local anesthesia plays an important role in controlling
blood osmolarity which may have a harmful effect if not regulated carefully (Annamalai
et al., 2012).
Neuronal Function and Signaling
Neurons play a critical role in relaying messages to and from the brain. A
significant amount of research has been done in the past to understand how neurons
work. Much of this information has been compiled into a single review by Huang and
Reichardt (2003). They begin their paper by writing that neurons use a very important

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integral protein family called the tropomyosin-related kinase (trk) receptors, especially
TrkA. More about tropomyosin-related kinase receptors was discovered when the first
nuerotrophin known as Nerve Growth Factor (NGF) was identified. Its role in
intercellular communication was found during experimentation with cells in a process
known as ablation, which removes targets of interest from the cell surface in an attempt
to show the function of the removed structure. Another form of studying cell surface
proteins used transplantation to move TrkA receptors from one neuron to another neuron.
In each case it was discovered that NGF was either produced in larger amounts than usual
via transplantation, or NGF production stopped via ablation. NGF works as an internal
signal that affects both nuclear regulation and intracellular signal pathways.
The main functions it has within a cell are to control growth cone motility usually
located at the axon terminals (seen in Figure 6), and to regulate gene expression of
neurotransmitters. The function of such neurotrophins could not be realized if TrkA had
not been discovered prior to its investigation. The pathways controlled by neurotrophin
activation of trk receptors include: directionality and growth of the ends of the neuron
(dendrites and axon terminus), controlling the overall structure of the cytoskeleton,
creation of the synapse along with its function and flexibility, control of movements of
the cell membrane, proliferation of the neurons, and helping with overall survival of the
cell (Huang and Reichardt, 2003).

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Figure 6. Growth Cones in Neurons (Kamiguchi, 2005).
While trk receptors, TrkA, TrkB, TrkC, are very similar in functionality and
structure, they bind specific sets of signals unique from each other because of unique
small sequences of amino acids that determine different activation domains for each
receptor. Receptor specificity is enhanced by the presence of a protein called p75NTR
.
Truncated tropomyosin-related kinase receptors have unique effects when interacting
with full length trk receptors. When truncated trk receptors are located on nonneural
cells they have the ability to accumulate neurotrophins and present them to nearby full-
length trk receptors to activate them. When truncated trk receptors are located on
neuronal cells that also have full-length trk receptors the neurotrophins are inhibited by
the formation of nonproductive heterodimers between the truncated and full-length trk
receptors. For neurons directly responsible for the Central Nervous System (CNS) trk

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receptors are enclosed in intracellular vesicles until the cell is stimulated by stimuli that
determine the receptors will be necessary in an intercellular signal transduction response.
The stimuli responsible for this include: the Ca2+
endocytosis, cAMP presence, and
electrical stimulation, which all trigger the exocytosis of vesicles containing trk receptors
leading to the insertion of these proteins into the cell membrane (Huang and Reichardt,
2003).
Trk receptors are unique from other types of tyrosine receptor kinases because the
extracellular domain has an arrangement of 3 leucine-rich sequences approximately 24
amino acids in length with a cysteine rich motif on either side of the leucine sequences,
as seen in Figure 7. Nearby the cysteine rich regions there are two C2-type
immunoglobulin-like domains present. These domains are most similar to mammalian
T-cell extra-membranous antigens used in cell-cell communication and cell recognition
(EMBL-EBI, 2015). Moving inward to the intramembrane portion of the receptor there
are a few tyrosine kinase domains as well as domains that have tyrosine as the main
amino acid involved in their active sites that function similar to other types of tyrosine
kinases.

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Figure 7. A model of the TrkA receptor (Look for Diagnosis, 2014).
The main binding domains of the extracellular trk receptors are the
Immunoglobulin-like domains where neurotrophins will attach and start the signal
transduction pathway. Neurotrophin specificity for the different trk receptors is highly
dependent on the protein structure closer to the amino-terminus. Interestingly once
bound to the trk receptor a few neurotrophins are able to change their structure slightly
allowing them to activate different types of trk receptors once their original job has been
accomplished. This recycling of ligands is able to activate multiple receptors and
various receptor types for responses to various stimuli when necessary. Huang and
Reichardt (2003) have also found that the cysteine-rich and leucine-rich extracellular
domains of the trk receptors contribute to the binding of ligands. Further studies have

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confirmed the role of the Immunoglobulin-like domains by removing them to study the
overall effects, and found that the mutants created had much higher chances of
spontaneous dimerization and activation of the tyrosine kinases.
While neurotrophin shapes are important for specificity of which trk receptor they
bind to, the actual shape of the trk receptor also plays an extremely important role. This
is regulated by the pan-neurotrophin receptor known as p75NTR
, which is an integral
membrane protein. Experiments indicated that NGF binds to TrkA in the same manner
regardless of the presence of p75NTR
, but it also binds much slower. This indicates that
p75NTR
is an enzyme or cofactor of an enzyme that assists with the binding process to
active trk receptors. Further studies have also found that p75NTR
does not need to be in
the correct conformational structure, but its presence alone is enough to initiate a high
affinity binding between the neurotrophins and trk receptors. Recently researchers have
found that trk receptors can also be activated by the coupling of PAC-1 and
AdensoinseA2a G-coupled receptors. While this method does work, the process is much
more time consuming and impractical in cells since this activation process takes a few
hours to achieve, while it is inhibited by Ca2+
ions that have been bonded to other
molecules, but it is also unaffected by protein kinase A and protein kinase C inhibitors.
Once activated trk receptors dimerize to allow the phosphorylation of several
tyrosine kinase domains located on the receptors intracellularly. Phosphorylation of
these and additional tyrosine kinases creates docking sites for additional proteins within
the cytoplasm. Phosphotyrosine-490 binds to various types of other adaptors, with the
most prominent being ras and PI3 kinase that are used to regulate the cell cycle and cell
proliferation. Phosphotyrosine-785 binds to PLCG1, which helps activate PI3 proteins.

27. 27
In addition, studies have shown that trk receptors are still active even without
phosphorylating the cytroplasmic domain tyrosines because of an interaction between a
tyrosine kinase called c-Ab1 that binds to the basal membrane very close to the trk
receptor (Huang and Reichardt, 2003).
Tyrosine-785 phosphorylation leads to the binding of PLCG1, which then has
conformational changes occur that allow for reactions with phosphatidilinositol 4,5-
bisphosphate to hydrolyze it into diacylglycerol, known as DAG, and inositol tris-
phosphate, known as IP3. Diacylclycerol is used to activate DAG-regulated protein
kinase C, while the main function of IP3 is to instigate the release of Ca2+
from vesicles
within the neuron into the cytoplasm, which then activates enzymes, such as protein
kinase C. When TrkA is activated by the binding of NGF a signal a series of
mechanisms takes place within the nucleus that allows for the activation of sodium
channel genes for prolonged periods of time lasting as long as a few hours.
Phosphoinositide 3 (PI3)-kinase is used to help create P3-phosphorylated
phosphoinositide, which is helpful in determining the survival ability of a neuron. This
molecule is used to help activate phosphatidylinositide-dependent protein kinase (PDK-
1), which then works to activate a protein kinase known as Akt, as seen in Figure 8.
This process leads to a series of other protein kinase activations that eventually lead to an
increase in a cell’s survival. Ras activation also allows the activation of Class I PI3-
kinases. Most trk receptors will follow this pathway in an attempt to encourage cell
proliferation. The activation of PI3-kinase also promotes phosphorylation of Grb2,
which then activates the Gab1 and Gab 2 proteins. These proteins are used for the
creation of Shp2 tyrosine phosphatase used for increasing the activity of MAP kinases.

28. 28
Some of the proteins involved with Akt are also used in the cell signaling pathway that
leads to apoptosis. The proteins produced are meant to work as anti-apoptotic signals
that prevent apoptotic proteins, such as Bad, from working. These proteins, known as
the 14-3-3 proteins, bind to Bad at its Serine (S)136 region to help expose a
phosphorylation site at its S155 location and when phosphorylated it prevents Bad from
binding to the Bcl-XL protein, which would normally signal the beginning of apoptosis
within the cell. Cell survival is promoted by the activation of MAP kinases that help to
phosphorylate Bad at S112 to also help increase exposure of its S155 location. Another
pro-apoptotic protein is known as glycogen synthase kinase 3-beta, which is regulated by
Akt in a similar manner to Bad. Akt also phosphorylates the IKB that produces NFKB,
which is necessary for cell survival since it supports neuron survival. Essentially, Akt is
an important protein used for the phosphorylation of pro-apoptotic proteins to promote
cell survival (Huang and Reichardt, 2003).

29. 29
Figure 8. A model of the signaling pathway expressing PI3-kinase and its function
(GeneCopia, 2015).
Neurotrophins are interesting because they are often produced in a neuron, then
transported to other parts of the body that may not be located within the general vicinity
of the origin. In order for the neurotrophins to bind to the cell, they must attach to
suitable extracellular domains of the trk receptors. The trk receptors are found in high
concentrations in ingavinated lipid rafts, or caeoli, of the membrane. Once
neurotrophins bind to the receptors, the newly formed protein complex moves inward to
the cytoplasm using clathrin-coated pits, which can be seen in Figure 9. This complex
is bound by endosomes that also contain intermediate signal proteins such as PLCG1,
which then allows for the phosphorylation of those proteins. The endosomes are then
transported to either the nucleus or cytoplasm, depending on what type of signal has been

30. 30
received by the neurotrophin. There were additional recent studies performed that
found neuronal cell survival can occur without the endocytosis of neurotrophins, such as
NGF. They are able to get around this mechanism because they allow for the lateral
activation of the trk receptors with subsequent trk receptor endocytosis and the continued
signaling pathway. The type of signaling pathway is determined by the location of the
original trk receptor along the membrane. Another possibility of having a different
signaling pathway is by having a different protein coat the entering NGF-trk protein
complex. The other protein recently discovered is known as Pincher and it promotes
pinocytosis (Huang and Reichardt, 2003).

31. 31
Figure 9. Receptor-ligand complex formation with clathrin-mediated endocytosis
(Carroll, Beattie, Von Zastrow, and Malenka, 2001).

32. 32
Overall, the signaling pathway is used by all neurons within the body. When
neurotransmitters attach to surface receptors, a series of signals are activated
intracellularly that enable a message to be relayed between multiple cells within the
vicinity of the target area. Local anesthesia works by competitively inhibiting
neurotransmitter signaling between cells as it attaches to the integral receptors and
prevents a change in potential across the membrane. The lack of signaling masks the
perception of pain to give patients much needed relief when they enter a dental office and
have major surgery performed on their teeth (Huang and Reichardt, 2003).
Allergies to Anesthesia: A Case Study
Tooth decay and other issues sometimes remain undetected until a noticeable
symptom makes itself present. This is not always the case, especially when the victim
of such an issue is relatively young and unable to express themselves properly.
Situations can be made more complicated when unknown allergies present themselves at
inopportune times. Allergies present a very serious threat in the health field when trying
to provide treatment for patients, especially while there are very few alternative options
for that treatment.
There has been one case reported by Doko, Iranami, Fujii, Yamazaki, Shimogi,
and Hatano (2009) regarding a severe, near-fatal allergic reaction one infant experienced
after being administered with a regional anesthesia. In this case the patient was an 18-
day-old girl referred to a pediatric dentist because of her already erupted neonatal teeth
on the upper and lower jaw. The dentist decided that it would be in the best interests of
the mother and infant to have the teeth surgically removed because of severe gingival

33. 33
infection surrounding the teeth, which posed a greater risk of causing the infant’s heart
disease to recur. The girl had no known allergies to any type of anesthesia previously
used for her heart surgery, so it was assumed that she would be fine to use other types of
anesthesia for her dental surgery. Upon the initial injection of anesthesia the girl
showed no signs of an allergic reaction, nor were there any signs during the extraction.
Approximately 1 hour after the injection she began developing central cyanosis and was
unresponsive to oxygen treatment. The girl was diagnosed with methemoglobinemia
after she was treated for her cyanosis. Methemoglobinemia is a condition in which the
iron of hemoglobin in red blood cells becomes oxidized and is unable to release oxygen
to organs once it has come in contact with it (Medline Plus, 2015).
It is believed that the girl suffered from methemoglobinemia as a result of the
anesthetics administered to her before and during her teeth extraction surgery. The
focus of attention for this research group was based on the anesthesia called Citanest-
Octapressin® with an active ingredient of prilocaine. Prilocaine side effects have
already been documented in past research and clinical trials, and were labeled as
dangerous because it has a higher risk of causing methemoglobinemia in infants.
Prilocaine causes oxidation of hemoglobin to occur, which then transforms it into the
inactive methemoglobin form. Infants have particularly vulnerable hemoglobin
compared to adults, which makes it harder to gauge the proper amount of anesthesia
necessary to make them comfortable while operations are being performed. Doko et al.
(2009) believed the infant suffered from methemoglobinemia because there was an
overdose of it being used on the girl. It has been stated that Citanest-Octapressin® is
known to be more dangerous than other anesthesia and should be avoided when possible.

34. 34
The True Role of Histamines
Allergic reactions have varying degrees of severity, with a strong dependence on
what type of allergen the person suffering from the allergies has been exposed to. They
happen to people of all ages, and many times they are developed later in life once a
person has been in contact frequently with that allergen. In a review by Thurmond,
Gelfand, and Dunford (2008), the role of histamines in white blood cells has been
discussed as its role in the creation of allergic reactions is extremely important, as well as
its more natural function in preventing infections. Thurmond and colleagues state that
histamines had been discovered along with their primary function in the early 1900s.
The side effects from large histamine coaggregation commonly include itchiness,
puffiness, redness, and swollen feeling under the skin, while a more extreme example is
an anaphylactic shock. Other functions of histamines include signaling for gastric acid
secretion in the stomach, and acting as a neurotransmitter for other cells.
Histamines are released from Basophils and Mast cells when responding to
allergens, as seen in Figure 10. The main targets for action are the endothelial cells and
smooth muscle cells. Their presence in the blood stream allow for tightening of veins,
or vasodilation, which causes a rush of red and white blood cells to the area giving it the
inflamed appearance and feeling. In addition, the vasodilation stretches the cells in the
veins slightly apart making it easier for white blood cells to move between the cells of the
skin to fight infections. Histamine is used by the gastrointestinal tract to release gastric
acid when enterochromaffin-like cells are stimulated by gastrin. After stimulation of
those cells, histamines are released to act on nearby parietal cells to trigger the release of
Hydrogen ions and potassium ions to cause a decrease of pH in the stomach, which helps

35. 35
in the process of food digestion. Histamines are also used as neurotransmitters in the
central nervous system (CNS), which functions to control learning and memory, hunger,
and the cycles of sleep. Histamines have been found in elevated numbers in numerous
other diseases, such as atopic dermatitis and rheumatoid arthritis, but traditional
antihistamine treatments used for these diseases have not been successful. From the
time of the discovery of the link between these diseases and histamines scientists have
been studying the role histamines play in disease formation, and have discovered there
are 4 different types of histamine receptors on a cell. The most recently found is the H4
receptor that is used for the inflammatory response in the body (Thurmond et al., 2008).
Figure 10. An overview of an allergic reaction (Saddleback Church, 2011).

36. 36
Histamine receptors are all identified as G-protein coupled receptors that are quite
unique from each other, with estimates of their similarity as low as 16-35%. What is
unique is that the H4 receptor appears to be specialized for each species and has a
homology of 65-72% between species. Each of the different types of histamine
receptors have been researched to find what happens during after substrate-receptor
complex formation. The H1 receptors are used to create inositol phosphate, activate
phospholipase C, and allow for calcium transportation. H2 receptors allow for an
increase in cyclic AMP (cAMP) formation as well as activating G alpha proteins. H3
receptors utilize G alpha proteins to activate mitogen-activated protein kinases (MAPK)
in addition to ion channels. They are used to inhibit cAMP formation, and are used to
help increase calcium transportation within a cell. H4 receptors are coupled with G
alpha proteins used for detection of the pertussis toxin and is measured by the amount of
calcium concentrations intracellularly (Thurmond et al., 2008).
The H1 receptors are found on a variety of different types of cells, while some of
their most prominent functions are to control vasodilation and the tightening of the
muscles around the airways, known as bronchoconstriction. First generation
antihistamines that were created have a sedation effect because they block off most
functions of the H1 receptors and are particularly strong in their ability to turn off the
histamine interactions used in regulating the sleep cycle. H2 receptors are also found on
various types of cells with their main function being the control of gastric acid production
in the stomach and gastrointestinal tract. They were discovered because researchers
found that histamines were still binding to cells despite the use of anithistamines on the
H1 receptors, and their existence was proven by the creation of ligands that were specific

37. 37
for the H2 receptors while they did not bind successfully to any of the other receptors.
The H3 histamine receptor was discovered when inhibitory drugs developed for H1 and
H2 receptors were unable to prevent histamine binding completely (Thurmond et al.,
2008).
The function of the H3 receptor was found to be a neurotransmitter inhibitor that
also had the ability to prevent other histamines from being produced. These receptors
were found to be mainly on neurons and other cells within the nervous system. They
work as presynaptic receptors that assist with intercellular neurotransmitter
transportation. Recent studies have also found that these receptors allow for
neuroinflammation, which is responsible for causing a number of neurological disorders,
such as obesity or insomnia if the inflammation is chronic. The H4 receptor was found
in a different manner than the other histamine receptors. Researchers were attempting
to sequence out the other 3 receptors and coincidentally discovered a fourth genetic
sequence that was quite different from the other 3. The H4 receptor is found mainly on
cells that originate from bone marrow known as hematopoietic cells. Since H4 receptors
are so unique drugs that inhibit the H1 and H2 types of receptors have no direct effect on
the H4 receptors, while certain inhibitors for the H3 receptors are quite potent. In
general it has been found that cells involved in allergic responses will express the H1, H2,
and H4 receptors on their cell surfaces. All H receptors and functions studied can be
seen in Table 5.

38. 38
Table 5. A comparison of histamine receptors and drug interactions (Thurmond et al.,
2008).
Histamines in allergic reactions are produced primarily by mast cells— cells
found in mucosal membranes— and basophils. Histamines that use the H4 receptors are
able to initiate chemotaxis, cellular movement, in mast cells and are able to control the
distribution of those cells within mucosal parts of the body leading to the nasal
inflammation, or rhinitic response, caused by allergen presence. In addition, H4 receptor
activation allows for the chemotaxis of eosinophils while it promotes the formation of
superoxides and actin reconfiguration. Dendritic cells, used in antigen signal
processing, are controlled in movement by the activation of H4 receptors, which can

39. 39
further act on the different types of T-cells in the blood. It is interesting to note that
studies have not found a definite effect of histamines on the overall production of T-cells
in their presence as data has shown they can increase the production of T-cells if just the
H1 receptors are activated, while they can also inhibit T-cell production if only the H2
receptors are activated. Histamines are able to control the junctions between different
epithelial and endothelial cells to allow extra movement of leukocytes between the target
cells through the process of diapedesis (Thurmond et al., 2008).
Allergic responses by the immune system are very important to understand both in
cause and regulation of symptoms. For many years before the use of microscopes and
the study of immunology people have experienced these reactions in varying levels of
severity. It is unknown why some people have heightened sensitivity to certain
allergens, while others may never experience allergies throughout their entire lives, while
even others may develop an allergic reaction later on in their lives. This is extremely
important to keep in mind as a dentist since many times different types of chemicals are
used and applied to areas of the mouth that may have a high chance to enter the
bloodstream directly, and have negative effects occur, such as severe allergic reactions.
Allergies to Office Supplies
Dental surgery in children is difficult particularly because of their inability to
cooperate properly with the directions given by the practicing dentists. One of the few
things that are not often thought about that make that challenge much harder is the
involvement of a mental disorder that impairs judgment further, such as spina bifida—
the incomplete development of the brain, spinal cord, or protective covering, known as

40. 40
the meninges, that is also the most common congenital neural tube defect in the United
States (NINDS, 2013). Neurological diseases impede a child’s ability to cooperate with
authoritative figures because the diseases will often cause inhibition of the cognitive
thought processes. The inability to cooperate has been linked with much higher risks of
the formation of serious dental problems. This has been recognized as a serious issue by
Hudson (2001), which instigated her research. Hudson explained that children afflicted
with neural tube defects, especially spina bifida, had a much higher risk of being allergic
to latex exposure. They often have a very high risk of latex allergies ranging from 28-
67% and symptoms appear with even the slightest contact with the allergen on mucosal
membranes.
Spina bifida has 2 major forms that are known as spina bifida occulta— the closed
form with a characteristic growth of hair— and myelomeningocele— the open form that
has growth of the spinal cord protrude from the dorsal side of the body.
Myelomeningocele is considered the most severe of these diseases because it presents a
large health risk of having part of the spinal cord along with the fluids surrounding it
bulge into a pocket of skin that is extremely sensitive to different forms of stimulation
and is most often associated with paralysis. The sac that forms is also highly susceptible
to infection making it a priority for many doctors to perform surgery the moment the
disease is identified as the open form. Surgery is performed before the nerve cord has a
chance to enter the sac formed, as seen in Figure 11.

41. 41
Figure 11. Spina bifia occulta (A) and spina bifida myelomeningocoele formation (B)
with complete myelomeningocoele (C) (Biology Forums, 2015).
The interaction between spina bifida and latex allergies has been an increasing
concern for dentists and researchers for the past couple of decades. It is still not known
what causes the allergic reactions, only that there are 3 major types of reactions that come
from contact with it. The types of reactions are: contact dermatitis, allergic contact
dermatitis, and immediate hypersensitivity. Contact dermatitis is the least dangerous of
the allergic reactions and the symptoms include itchy, red, scaly feeling skin that has
come in contact with latex. Allergic contact dermatitis is more harmful than contact
dermatitis, while it is still less harmful than immediate hypersensitivity.

42. 42
Allergic contact dermatitis gives the sufferer stronger redness, itchiness, and blistering of
the skin within a 48 hour timeframe after the person has come in contact with latex.
Immediate hypersensitivity occurs as a result of the body’s production of
immunoglobulin E (IgE) when the skin comes in contact with any form of antigen and
can cause severe, life-threatening symptoms, such as anaphylaxis when untreated.
Because of the variety of allergic reactions that can potentially occur in children
with spina bifida, parents and guardians are strongly encouraged to have the child be
tested prior to their first oral surgery. Since latex is so commonly used in a variety of
different medical devices, as seen in Table 6, parents and guardians must be extra careful
to let their dentist know of any allergies. Testing for allergies often is the best course of
action for those affected because the allergies can develop suddenly without any prior
symptoms. With latex allergies being fairly common in even healthy individuals, dental
offices are required to have latex-free facilities to help protect the health of all their
patients. Another suggestion for patients suffering from this disease is that they wear a
wristband identifying them as having latex allergies so the operating dentist will always
be able to check the condition of the patient even when the patient is unable to confirm
their status (Hudson, 2001).

43. 43
Table 6. A list of commonly used medical equipment containing latex (Hudson, 2001).
Danger Involving Injections
A review of anesthesia by oral injection was written by Smith and Lung (2006) to
help other dentists understand the importance and possible risks of the use of needles
with anesthesia in dental work. The main concern is the direct contact of the needle to
the neuron. The lingual, or tongue, nerve is located approximately 3 to 5 mm behind the
surface proximal to the oral cavity, viewable in Figure 12. When the mouth is opened
for the dentist to administer the injection, the nerve is held tightly in place. Because of
this the nerve loses its ability to be flexible and is unable to evade the penetration of the
needle if it is in the direct pathway of injection. The most common technique of

44. 44
injection requires the needle tip to reach the jawbone before the dentist releases
anesthesia to the jaw. A very concerning issue is that the needle is often damaged once
it reaches the bone and becomes barbed, much like a fishing hook. The barbed needle
then has a much higher chance of damaging all types of tissue upon removal from the
gingiva, especially the extra-sensitive nerve tissue. The typical damage caused by
barbed needles has been classified in a range from axonotmesis to third-degree nerve
damage. This damage is thought to be temporary because the average neuron is 1.86
mm in diameter, while the thickest needle allowed to be used in dentistry is 0.45 mm,
roughly ¼ the size of the neurons. It is strongly believed that with these facts there is
almost no chance of permanently damaging all parts of the nerve tissues upon a single
injection of anesthesia.
Figure 12. Image of the Lingual Nerve in the Mandible (Study Blue, 2014).

45. 45
Another thought on the possible damage caused by needles, as explained by Smith
and Lung, is that the blood will clot around the damaged neuronal tissue and the damaged
capillary beds. This hematoma can cause scarring of the penetrated area within the
gingiva and leads to inhibited neuronal recovery after the procedure has been completed.
Inhibition occurs because of pressure that builds up at the clotted area which in turn
damages the myelination of axons. The degree of injury depends highly upon the
body’s response to the injection. Remyelinization occurs slowly using the remaining
segments of the axon’s Schwann cells as a template. The nerves can grow up to 2 mm
per day, causing recovery to finish within several weeks.
Damage to the neurons may be permanent due to a number of different reasons
involved with either needle penetration, or with anesthesia application and complications
with the body’s ability to secrete the newly formed neurotoxins. The damage is put into
3 categories: anesthesias, paresthesias, and dysesthesias (Smith and Lung, 2006).
Anesthesias is described as the absolute loss of all feeling within the affected neuronal
area. Paresthesias is described as a type of normal feeling within the affected area with
occasional stabbing sensations described as a pricking by pins or needles. It is also felt
by some people as a mild electric shock that isn’t always painful, but is quite
uncomfortable since it occurs very abruptly. Dyesthesias has been described as normal
feeling within the affected area with an occasional strong painful feeling created either by
a certain form of movement, or it spontaneously occurs. Dyesthesias often has the
broadest range of side effects associated with it, which range from delayed pain response
(hyperpathia) to a strong painful response to non-painful stimuli (hyperalgesia).

46. 46
During penetration of the needle, strong electric shock feelings may occur if the
needle contacts the nerve trunk, seen in Figure 13, which does not have an increased risk
for permanent damage, and rarely occurs during insertion of the needle. It should also
be noted that 57% of patients who have experienced one of the previously mentioned
types of permanent injury also felt the shock during injection. The most probable
location for nerve damage is the tongue since the lingual neuron is most commonly
affected by the injection. Damage to the lingual neuron causes loss of taste and
sometimes loss of feeling in the mandible (lower) jaw. Prolonged loss of sense in the
lingual area is examined in a number of ways. One of the most common forms is by
performing taste tests. Lack of taste, or altered taste indicates nerve damage. Another
form of diagnostic test is a pin-prick test to determine how far the loss of feeling has
spread in the face. Typically patients will recover from the various forms of
neurotoxicity within 8 weeks of exposure. Surgery as an option for recovery is not
usually considered because there is little research supporting its use in patient recovery
(Smith and Lung, 2006).

47. 47
Figure 13. Cross-section of a Nerve Trunk (Jeunon de Sousa Vargas, Sousa, Sampaio,
Mourad, and Golttlieb, 2009).
Pains After Operations
While pediatric dentistry has shared concerns with general dentistry practices used
on adults, it also has its own unique set of protocols necessary to make a child cooperate.
After a surgery children tend to be very subdued and will not report any signs of distress
in fear that they may have to return to the dentist and have more operations done. A study
was done by Jensen (2012) in an attempt to find out just how much pain and suffering
children really experienced during and after procedures were finished. The study
looked for children between the ages of 3 and 12 who were being referred to specialized
pediatric clinics because of the severity of their dental caries, which caused a need for
extraction with no alternative options. After the operation parents and children were
given a survey to fill out over the next couple of days to document all forms of pain or

48. 48
suffering the child may experience. It should also be noted that some form of pain
medication was prescribed to all the patients after the surgery was finished for a
minimum of 2 days. The children’s pain was recorded using the face analogue scale
(FAS), visual analogue scale (VAS), and colored analogue scale (CAS) from either self-
assessment, if the child was capable of making the decision, or by the parent selecting
based on the facial expressions given by the child, which is viewable in Table 7. In this
particular study there were a total of 100 surveys returned after being properly filled out
with 51 boys and 49 girls as the patients evaluated.
Table 7. Comparison of pain evaluation in children post-operationally using various
types of visual scales (Jensen, 2012).

49. 49
It was found that the ratings of pain provided by the parents had not significantly
differed from the ratings the children gave for the pain expressed by each child after the
dental operation was finished. It was later revealed that the children who had
participated in this experiment had a long history of dental surgeries and it was possible
that these children adapted to different forms of pain management over time. This
would explain why the average pain values were so low when Jensen predicted they
would be higher. Even with low averages for pain on any given day, some children still
experienced very strong pain either directly after the surgery, or for the next couple of
days following the surgery, and the children who had reported the highest amount of pain
typically were the same children who reported higher levels of pain for the following
days. It was interesting that parents were able to accurately describe the levels of pain
the child experienced since they often have to evaluate the health of their child on a daily
basis, and are able to differentiate the act of feigning pain or having actual experiences
with it. Based on the parents’ perception of pain experienced by the children, many of
the children had not received the prescribed analgesic medications once they left the
dental office (Jensen, 2012).
It was estimated that roughly 29% of all parents had followed the dentist’s
recommendations to provide medication every day for the following few days. This
concept of parents avoiding the responsibility to give medicine to the children followed a
previous study in which the parents explained how they feared the negative side effects of
drugs and refused to put their child’s health at risk for a temporary relief of pain. There
has also been more evidence of parents disregarding the pain children experienced post-
operationally and even if they had recognized the pain as extremely prominent, most of

50. 50
the parents still refused to provide pain medication. This trend in parental neglect was
still present despite the use of self-reported pain scales by the children. It has been
suggested that parents may have the belief that pain medications should only be used as a
last resort even under professional recommendation to use it as often as necessary, while
it has also been suggested that this type of choice has been made predominantly in lower
educational households.
Jensen found it surprising that children in this study had relatively low levels of
pain experienced despite having multiple teeth extracted. It has been explained that the
possibility for lower pain ratings came from children who were more cooperative with
the dentists and generally didn’t have as much anxiety during the procedure. Many of
the children who experienced little pain after the surgery also seemed to be more tolerant
of pain in general, which allowed them to handle the perceived pain much better.
Jensen explains the pain could have been managed by parental intervention using
different forms of distractions that removed the child’s mind anytime they would have
felt uncomfortable.
An Alternative to Drilling: The Papyrus-based Gel
Since children are often much more affected by their fear of dental drills, finding
alternative methods of dentistry has been a growing concern. Maru, Kumar, Dadiyani,
Sharma, and Dobariya (2014) wrote an article that studied one of the alternative methods
performed in their dental office. The method studied used a form of chemomechanical
removal of caries using a chemical called Papacarie that was developed by a project in
Brazil led by Bussadori, Castro, and Galvão (2005). The sample size for this study was

51. 51
60 patients all between the ages of 3 to 5 who needed professional treatment to remove
carious lesions in their teeth. The study divided the patients into the control group that
had treatment using traditional drilling methods, and the experimental group that used the
Papacarie gel without the assistance of any rotary devices. For the patients receiving
Papacarie treatment the gel was administered to the tooth for roughly half a minute, then
the cariogenic tissue was removed using a spoon excavator with minimal pressure
applied, so as to not damage the unaffected tissue. This process was repeated once the
excavator was unable to dig deeper into the hole created. It continued until the gel no
longer had an impact on the tooth it was applied to, which indicated there was no more
decay present. The tooth was then treated with liquid Glass Ionomer Cement and
shaped to match the bite pattern of the mouth. This type of treatment, as well as
treatment from traditional rotary tools, did not involve the use of anesthesia.
The overall anxiety of the patients, average age 4 years old, was measured using a
system called the Modified Child Dental Anxiety Scale, and was measured in 4 different
phases of the overall treatment time: 5 minutes before the procedure, during the
procedure, immediately following tooth restoration, and 5 minutes following the end of
the procedure. It was found that there were significant differences in all the phases of
treatment, except for the actual procedure itself. This indicates that the method of
treatment itself had a great impact on the patients’ anxiety, but the effectiveness of either
method in caries removal was the same. Maru et al. (2014) suggested that the sharp
sound of a dental drill may have the largest influence on anxiety levels. By removing
the sound associated with the fear, dentistry can be performed on patients much more
easily.

52. 52
The development of Papacarie gel, whose predecessor was Papain gel, was
reviewed by Bussadori et al. (2005). Papain gel has an active ingredient, which
catabolizes collagen that has already started the process of degradation caused by
cariogenic bacteria. The original idea to use chemical removal of decayed tooth
material was created in 1975 using a 5% sodium hypochlorite solution to remove affected
tissue. It was also known at the time of the original study that the solution was quite
toxic and was nonspecific in its ability to remove collagen within dental tissue. Later
versions created contained N-monochloroglycine as a substitute for sodium hypochlorite,
but it was also much slower and not as useful at the time it was first developed. Another
form of chemical removal was called Caridex™, which combined the previous solution
with the addition of amino butyric acid. This was considered not as feasible in dental
offices because the formation of such a compound was expensive, required other
equipment to properly administer during procedures, a lot was needed for a single tooth
restoration, prevented drills from being used as normal since it was heat sensitive, and the
solution itself was unstable.
After the long process of attempting to find a good replacement, a new discovery
was made in 2003 in Brazil. This new chemical removal tool was known as Papacarie®
whose main active ingredient is papain, a proteolytic enzyme found in papyrus fruit that
has similar functionality as pepsin generated naturally by the human body. Papain also
helps by accelerating the natural healing process the tooth produces after experiencing
various levels of trauma. One of the key components of its functionality comes from the
removal of necrotic tissue. This happens because normal tissues contain al-anti-trypsin,
which helps prevent degradation of any proteins within a living cell by outside sources.

53. 53
Cells that have already been damaged are unable to produce as much of this protein, or
even no protein if the cell has already died, which then allows the papain to remove the
damaged tissue, as seen in Figure 14. The use of Papain in caries removal also helps to
speed up the recovery process after the procedure is finished, often making it the better
form of removal if the infection has not spread in close proximity to the dental pulp. A
study of ripe versus unripe Carica papaya yielded the same results of being able to
prohibit growth of gram positive and gram negative bacteria.
Figure 14. Application and use of Papacarie® in carious lesion removal. (Bussadori et
al., 2005).
Papacarie® is also mixed with chloramines, which have beneficial functions in
decay removal. Studies have revealed that chloramines have a significantly stronger
antiseptic effect than other commonly used compounds. It works by chlorinating
collagen to prevent proper folding at its quaternary and secondary structures by
interfering with hydrogen bonds between various amino acids. At the moment of

54. 54
collagen degradation, oxygen is released from the cell periphery, which causes a smear in
the coloration of the gel and slight bubbling from underneath the surface. The action of
strictly removing dead cells from the surface of live ones prevents the patient from
feeling most pain associated with dentistry, allowing for a faster and safer procedure
overall.
Conclusions
Dentistry is one of the best forms of medical care currently available. Because
of its popularity many issues associated with dental work have been studied. It has been
known that mental conditions have a strong influence on the effectiveness of treatments.
The use of needles in dentistry pose a slight risk of damaging tissues despite most
precautions dentists take to prevent it from happening. Needle insertion can be
performed a number of different ways to provide the best and most immediate relief
possible. To avoid negative side effects of needles rupturing connections between the
lingual neurons, many dentists have sought alternative methods of providing pain relief.
Using previous knowledge of how anesthesia interacts with cell surface receptors, new
forms of anesthesia have been developed and tested over the past couple of decades. All
methods currently available have their own defects compared to each other, but they are
each able to provide unique benefits as well. One of the most interesting methods is the
use of Papacarie® gel instead of a drill. It is immensely interesting to see how
knowledge and technology has developed so far within less than 100 years.
Dentistry is one of the most important components of today’s society. People
feel the need to adequately present themselves to others and make a lasting impression.

55. 55
One of the most important points they make is to have good oral hygiene when they
speak with others and participate in group activities. By having such a frequent need to
keep themselves clean, people return to dental offices frequently to fulfill such needs.
By having so many people visit with various problems associated with their mouths,
dentistry has become the cornerstone of all modern societies.

56. 56
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