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Local anesthetic agents
and their history
Surprisingly, the first local anesthetic was Cocaine which was
isolated from coca leaves by Albert Niemann in Germany in the 1860s. The very
first clinical use of Cocaine was in 1884 by (of all people) Sigmund Freud who
used it to wean a patient from morphine addiction. It was Freud and his colleague
Karl Kollar who first
 noticed its anesthetic effect. Kollar first
introduced it to clinical ophthalmology as a topical ocular (eye) anesthetic.
Also in 1884, Dr. William Stewart Halsted was the first to describe the injection
of cocaine into a sensory nerve trunk to create surgical anesthesia. Halsted was an
eminent surgeon who had been trained in Britain. He was the first to establish formal surgical training for
physicians in America. Prior to that time, surgery was a self taught discipline among
US physicians. He also invented and pioneered the use of rubber gloves.
Unfortunately, much to his own regret, he began to use cocaine himself and became highly addicted to
it. At that time, there was no stigma attached to the recreational use of
cocaine, and it gained a following among the elites of the day.
Arthur Conan Doyle's Sherlock Holmes was supposed to be an addict, and Holmes
kept Dr Watson around as a source for his drugs, as well as for the comic relief
he provided.
It became fairly obvious fairly quickly that while the
anesthetic characteristics of cocaine were desirable, the euphoria and
subsequent addiction it produced were not! The turn of the century was a
tremendous time of scientific progress, and the new discipline of
 organic
chemistry enabled the synthesis of the first analog of cocaine in 1905.
(An analog of a chemical molecule is one in which the original molecule is
progressively modified to retain and enhance certain holistic characteristics of
the original substance while ridding it of other unwanted
characteristics.) The first synthetic local anesthetic was procaine,
better remembered today by its trade name, "Novocain".
Novocain was not without its problems. It
took a very long time to set (ie. to produce the desired anesthetic result), wore off
too quickly and was not nearly as potent as cocaine. On top of that, it is
classified as an ester. Esters have a very high potential to cause
allergic reactions.
It is estimated that about one in 100 persons who received it developed at
least minor allergic reactions to it. Faced with the legal and ethical
difficulties associated with the use of cocaine as a local anesthetic, and with
the inefficiencies and allergenicity associated with the use of procaine, it is not surprising that most
dentists of the day worked without any local anesthetic at all. (Nitrous
oxide gas was available during this period.) Today, procaine is not even
available for dental procedures.
| In 1942, W.C. Fields made a movie called "The dentist". It
was a bawdy, slapstick comedy short (25 minutes) which included
scenes of Fields as a dentist working on patients, complete with the
sound of a buzz saw. It was, of course, meant to be funny, but
it shows a patient squirming in the dental chair, and in this sense,
at least, was probably not far from the truth about dentistry up
until shortly after the film was made. You can download a clip
from the film
here. (The link to the clip is near
the bottom of the page) |
 The first modern local anesthetic agent was lidocaine
(trade name Xylocaine®). It was invented in the 1940s.
Prior to its introduction, Nitrous oxide gas and procaine (plus alcohol in the form of
whiskey) were the major sources of pain relief during dental procedures. Lidocaine proved to
be so successful that during the 1940s and 1950s the use of procaine and nitrous oxide gas as
primary anesthetic agents all but vanished. (Whiskey somehow survived,
but it is no longer used on patients.) Today, nitrous oxide is used
principally as an anti-anxiety palliative, and Novocaine is no longer available.
Lidocaine (along with all other injectable anesthetics
used in modern dentistry) is in a broad class of chemicals called amides,
and unlike ester based anesthetics, amides are hypoallergenic. It sets quickly and when combined with a
small amount of epinephrine (adrenalin), it produces profound
anesthesia for several hours. Lidocaine is still the most widely used
local anesthetic in America today.
Over the next thirty years, a number of other amide local
anesthetics were invented, most not differing significantly from
lidocaine. The major problem with lidocaine and its analogs is that they cause vasodilation,
or the tendency of the local blood vessels to open wider increasing the blood
flow in the area. This causes the anesthetic to be absorbed too quickly to
take effect. Hence these anesthetics are always mixed with low
concentrations of epinephrine which has the opposite effect (ie vasoconstriction) and closes the blood vessels down to keep the anesthesia in
position long enough to produce long lasting numbness.
 Mepivicaine
(Carbocaine®) and prilocaine (Citanest®) have much less
vasodilative qualities and hence can be
used without the epinephrine vasoconstrictor. The advantage to this
is that these anesthetics can be used more safely in patients who are taking
medications which may interact negatively with the vasoconstrictor. These
drugs include certain blood pressure medications (most notably non selective beta blockers)
and tricyclic antidepressants (Elevil® and imipramine are two examples).
Carpules that do not contain the vasoconstrictor also do not contain a
preservative. This eliminates a possible source of allergic reaction.
Bupivicaine
(Marcaine®) Bupivicaine is a special case in dental
anesthesia. It is used mostly by surgeons who want to produce very long
acting anesthetic effects in order to delay the post operative pain from their
surgery for as long as possible. Bupivicaine comes in 0.5% solution with a
vasoconstrictor. It is the most toxic of all the anesthetic agents and this
toxicity is reflected in its low concentration in the carpules. As noted
in the PKa table, it is has a very alkaline (basic) PKa which means that a relatively
low percentage of the uncharged base radical (RN) is available for immediate diffusion
through the
cell membrane. Thus it takes a fairly long time to set.
However, once inside the cell membrane, over 80% of the radicals that do diffuse
become available for binding to the sodium channel proteins. This high
protein binding ability causes the drug to remain active for a long time once it
has diffused through the cell membrane. (PKa and its relationship
with cell membrane permeability is a concept explained
later in
this course.) The most frequent use of Bupivicaine is to prevent
post-operative pain after surgical procedures. Some dentists will inject a
carpule of Bupivicaine after an extraction in order to delay the onset of pain
for up to nine hours. This delay effectively reduces the period of severe
post operative discomfort which generally tapers off during the first 12
hours post op.
 Prilocaine
(Citanest®)
Prilocaine has the same general
PKa as
lidocaine, which means that for all practical purposes it can be used in the
same way and at the same concentrations as lidocaine, producing about the same
anesthetic affect in the same setting time for the same duration. It is,
however somewhat less toxic in higher doses than lidocaine, and thus is
delivered in a 4% solution which places about twice as much molecular anesthetic
in proximity to the nerve as is the case with lidocaine or mepivicaine. In
addition, since it has little vasodilatory activity, it may be used without a
vasoconstrictor. The higher concentration of anesthetic agent, in
combination with a vasoconstrictor, therefore, gives this anesthetic the twin
advantages of fast onset of activity with prolonged anesthetic activity due to
the larger number of molecules available to cross the cell membrane. Unfortunately, the toxicity of a single carpule of 4% prilocaine
is still greater than the toxicity of a single carpule of 2% lidocaine which
means that fewer carpules can be used before toxic levels are reached.
Higher toxicity also translates into a higher likelihood of prolonged or permanent paresthesia or
numbness after using this drug for major nerve blocks.
Articaine
(Septocaine®) Articaine is the newest addition to the local
anesthetic arsenal and was approved by the Food and Drug Administration in April
2000. It has been in use in Europe since 1976 and in Canada since
1983. Its approval in the US has been delayed by the FDA due to the
presence of a preservative which the agency said was unnecessary in single use
carpules and was a potential allergen. It was approved when the French company
Septodent finally removed the preservative from American shipments.  Articaine
has the same PKa and toxicity as Lidocaine, however it is metabolized
differently. It has a half life in the body less than 1/4 as long as that of
lidocaine and only 1/5 as long as mepivicaine. This means that more of the
drug can be injected later in the dental procedure with less likelihood of blood
concentrations building to toxic levels. Articaine is formulated
in a 4.0% solution with
vasoconstrictor. The presence of the
vasoconstrictor retards the systemic absorption of the anesthetic allowing
higher concentrations of the drug to remain in the area of injection and slowing
the absorption into the bloodstream. The higher local concentration of the drug produces a high level
of the uncharged radical (RN) to be present at the membrane which brings about
very rapid absorption of the drug. (The concept of membrane permeability
is discussed on page 4
in this course.) In addition, the benzene ring on the
left end of the molecule has been replaced with a thiophene ring. This
modification allows for faster and more complete absorption through the nerve
cell membrane. The ability of this drug to penetrate
barriers is so great that it has been used to penetrate thick bone to produce
anesthesia in a way that other anesthetics cannot. Articaine has become
the local anesthetic of choice in most countries into which it has been
introduced. I have found that it produces profound anesthesia (in
most patients) when used as an infiltration (field block) for mandibular
premolars and anterior teeth instead of the traditional mandibular nerve block..
With clinical reports of profound anesthesia, fast onset, and
success in difficult-to-anesthetize patients, Septocaine has become the most
used dental anesthetic brand name in the US, although lidocaine still remains
the most used type of anesthetic. Recently, the same articaine
formulation became available from a second company under the name Cook-Waite
Zorcaine.
Because of its bone penetrating ability, articaine has become
popular for producing profound anesthesia in lower premolars and lower anterior
teeth using localized field blocks (infiltrations) without resorting to
mandibular blocks.
Articaine and prolonged numbness and
paresthesia
Unfortunately, one complication concerning the use of articaine
has arisen. There have been persistent reports of unexplained paresthesia
(burning, tingling, and sometimes sharp shooting pains in tissues previously anesthetized with this anesthetic)
in a low percentage of patients. This effect has been noted
only when articaine is used in
major nerve blocks such as the mandibular block. It has not
been noted in
field blocks. So far, no common factor has been
found to explain the link between articaine and persistent paresthesia, however
the higher concentration of anesthetic molecules in the anesthetic solution
(4% for articaine instead of 2% for lidocaine or 3% for mepivicaine without
vasoconstrictor) probably is a factor.
The statistics produced for this phenomenon so far have been quite
inconsistent. The incidence for persistent paresthesia have ranged between
1 in 5,286 for 2002 to 1 in 45,900 in 2004. The incidence for persistent
paresthesia for other types of dental local anesthetic solutions ranged between
1 in 25,850 to 1 in 68,675 during the same timeframe (all statistics
approximate; CRA June 2005; vol 29, issue 6).
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10% of cases of paresthesia lasted for 24 hours or less.
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52% of cases of paresthesia lasted 1 to 4 weeks.
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29% of cases of paresthesia lasted 1 month to 1 year.
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10% of cases of paresthesia lasted for over a year.
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The most common link with articaine and paresthesia was
administration of mandibular nerve block injections. For this reason a
number of dentists have abandoned the use of articaine for mandibular nerve
blocks, but still use it for infilatration anesthesia (field blocks) of mandibular anterior
teeth and bicuspids.
In defense of articaine, it should be noted that prolonged
paresthesia and numbness are very uncommon occurrances, and the chances of
getting this type of injury are quite slim. Furthermore, 75% of these
cases are associated with the lingual nerve (the one that makes the tongue
numb when you get a lower tooth filled). This leads one to question
why this should be the case when the vast bulk of the anesthetic solution is
actually delivered at the site of the inferior alveolar nerve while only a
few drops are delivered to the lingual nerve while withdrawing the needle.
If the anesthetic itself is the culprit in the paresthesia, it would make
sense if the symptoms should occur more frequently in the distribution of
the inferior alveolar nerve (the chin, lip and teeth) rather than in the
tongue.
Finally, many dentists are beginning to use articaine for
mandibular blocks since this anesthetic produces vastly fewer anesthetic
failures than lidocaine or mepivicaine.
Treatment of anesthesia and paresthesia
I am not aware of any specific way to treat the numbness
caused by Articaine (other than waiting out the effect), however the
disruptive and often painful paresthesia, including the shooting pains in
the distribution of the affected nerves may be controlled with certain anti
convulsant drugs. One such drug is Lyrica (Pregabalin) 50 mg.
three times a day. Two older drugs in this category are Neurontin (gabapentin)
and Tegretol (carbamazepine).
Next
page==>Vasoconstrictors
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