LOCAL ANESTHETICS AND VASOCONSTRICTORS
AS THEY PERTAIN TO DENTISTRY
By H o w a r d C . M il l e r ,
U R IN G recent years, much re­
D search and experimental work have
been done in an effort to produce
a perfect local anesthetic solution, and
whatever future advancement there m ay
be in the use o f local anesthetics will
undoubtedly be toward the perfection of
the solutions that are to be injected.
In view o f the fact that our technical
procedures are based entirely upon ana­
tomic relations in the human skull, it is
obvious that there cannot be much varia­
tion in the manner o f injection. O cca­
sionally, refinements in technic are offered
by attempts to simplify the methods of
injection, but in most instances these are
based upon the procedures followed by
those who first presented the technic for
blocking various branches of the fifth
cranial nerve.
In the past, attention has been called
to the importance o f using a solution
which is isotonic, and the necessity for
using calcium, sodium and potassium
chlorides, such as are contained in a pre­
pared Ringer’s solution, for the anesthetic
vehicle. O n ly during the past few years
has the importance o f the hydrogen-ion
concentration o f the solution to be in­
jected been emphasized.
Clinical investigation has not substan­
tiated all the claims o f the advocates of
alkaline solutions, it appearing that the
pH of any injected solution will be rather
rapidly adjusted to normalcy by the buf-
(R ea d before the Section on O ra l Surgery,
Exodontia and Anesthesia a t the Seventy-
N in th A n n u al Session o f the A m erican D ental
Association, A tla n tic C ity , N . J., Ju ly 14,
I 937-)
Jour. A .D .A. & D. Cos., Vol. 25, March 1938
D .D .S., F .A .C .D ., Chicago, 111.
fer action of the body tissues and fluids.
T h e pH o f tissues locally is by no means
so easily disturbed as we have been led to
believe, although ample experimental
data, obtained under conditions more
adaptable to accurate objective evalua­
tions than are possible under clinical test
conditions, indicate that the development
o f anesthesia is more rapid and the dura­
tion o f complete anesthesia increases
significantly as the pH o f the local an­
esthetic solution increases to a maximum
of pH 8.4 to g.o.1’ 2- 8- *• 5
From a theoretical as well as from a
practical or experimental standpoint, the
efficiency o f the salts of local anesthetics,
alkaloids, etc., is enhanced when the com­
pounds are present as the base. When a
solution containing a local anesthetic
agent and a vasoconstrictor is combined
with an alkali, the alkaloid or base is more
readily liberated; which facilitates the
absorption and penetration o f the active
principle. However, the change in the
character o f the anesthetic solution under
these conditions is important from an­
other standpoint, as such a solution is less
stable, saponification o f the anesthetic to
an inert compound (p-amino benzoic
acid) tends to occur and the degree of
change increases m arkedly with time. The
degree of deterioration is governed pri­
marily by the degree o f alkalinity present
as well as by the age of the solution. Such
changes do not increase the toxicity, but
do render the anesthetic compound more
inert.
Tainter et al.,6 in their clinical com­
parison o f a 2 per cent solution of pro­
caine hydrochloride and a 4 per cent
391
 T a b le I.— S u r v e y o f L o c a l A n e s th e tic s *

Intraspinal Effects
Anesthetic Efficiency

Compounds Rabbit Cornea Local Minimal M.L.D. M.L.D. Estimated

Hydrochloric (Mucous Membrane) Irritation Concentra­ Thera­ Mg. per Kg. Mg. per Kg. Safe Dose
Acid Ratio to 1 Duration Greatest tion for M .L .D 4 peutic Subcutaneously Intravenously for Man
Salts Cocaine = 1 . 1 Minutes (1) to Least Sensory Ratio# Guinea-Pigs Rats Mg.
Anesthetic (Subcutaneously)

I II III IV V VI VII VIII IX X

Per Cent Per Cent

Procaine 0.06 5 6 0.9 6.0 6.6 350-600 55 430

Tutocaine 1 to 2 25 3 0.5 6.0 12.0 116-271 — 193

Panthesine 0 .5 — 5 0.5 4 .0 8.0 75-150 — 112

Metycaine 1.0 60 4 0.86 3.5 4 .0 — — 100
Alypin 0.5 — - — — — 60-100 15 72

Butyn 2.0 30 3 — — — 70 12.5 70

Phenacaine
(Holocaine) 2.0 20 2 — — — 50-60 — 53

Cocaine 1.0 30 - — — — 20-80 15 50

Pontoc.aine 30.0 85-120 2 0.05 1.5 30.0 — 7.5 20

Nupercaine 30.0 45-90 1 0.07 0.8 11.4 7.5-15 2-5 11
*Data adopted from publications by R. N. Bieter et al., 1936; Hirschfelder & Bieter, 1932.
fEqual volumes were injected in all experiments.
^Minimum lethal dose.
#Data column VI
—r-----------------------------------------:---------- rr- = Lolumn Vl l .
D ata column V
The Journal of the American Dental Association and The Dental Cosmos
Miller— Local Anesthetics and. Vasoconstrictors
solution of procaine borate (which con­
tains 51.8 per cent of procaine base) as
local anesthetics, concluded that on the
basis of procaine per se, no differences
between the two compounds were demon­
strable as to the volume of solution re­
quired or the period of time required for
the induction of anesthesia or its duration.
Likewise, certain side effects, i.e., changes
in blood pressure, pulse and respiratory
rates, from the two solutions were prac­
tically identical, both causing small av­
erage increases in pulse, respiration and
systolic blood pressure ; but the incidence
T a b l e 2 .— I n f i l t r a t i o n A n e s t h e s i a :
Compound Minimal Anesthetic
Concentration
Per Cent
Butyn 1/128-1/64
Cocaine 1/64-1/32
Procaine 1/64-1/32
Nupercaine 1/640-1/160
3.1 cc. intradermal.
T a b l e 3 .— N e r v e B l o c k :
Compound Minimal Anesthetic
Concentration
Per Cent
Butyn 1/32-1/16
Cocaine 1/4—1/2
Procaine 1/4—1/2
Nupercaine 1 /4 8-1/6
of perspiration, nervousness, tremors and
fainting was almost twice as frequent
with the borate as with procaine hydro­
chloride. T he concentration o f epineph­
rine used (1:50,000) was the same in
the two solutions injected.
Their findings compare favorably with
the electrocardiographic study reported
by M iller, Stuart and D ick,7 in which in­
jections were made with procaine borate
combined with epinephrine in a compara­
tive study of the individual patient’s re­
action to various local anesthetic solutions.
During this investigation, electrocardio­
grams were made before and after the
393
injection of the solution, and in the five
cases in which procaine borate with epi­
nephrine was injected, the average in­
crease in the heart rate was eleven beats
per minute and the rhythm was not al­
tered, but there were definite T-w ave
changes in all five cases. O ur experiences
indicate that the use of procaine borate
and procaine hydrochloride in equal con­
centrations has . similar local effects,
which, in the volumes used, were indis­
tinguishable. This practical experience,
when considered in conjunction with that
of Tain ter and his co-workers, seems to
W h e al T e st * (M a n )
Efficiency Ratio Toxicity
(Cocaine = 1) (Cocaine = 1)
2 1 .0 -1 .5
1 1.0
1 0 .1 4 -0 .2
5 2-5
F r o g S c ia t ic N e r v e T e s t
Efficiency Ratio Duration of Action
(Cocaine = 1)
8 1
1 1
1 1
3-12 3-12
indicate that the facts regarding acid and
alkaline solutions are quite incomplete, in
that, in our experience, little variation in
the promptness and intensity of anesthe­
sia, postoperative discomfort or other
complications can be traced to the pro­
caine solutions used, regardless o f whether
they are on the acid or the alkaline side.
Since 1884, when R oller first described
the local anesthetic effect of cocaine, the
history of local anesthesia has been
marked by an effort to eliminate all ob­
jectionable effects. In 1901, advantage
was taken o f the vasoconstricting prop­
erties o f epinephrine to delay absorption
394 The Journal of the American Dental Association and The Dental Cosmos
of the anesthetic agent, thereby prolong­
ing anesthesia and diminishing the tox­
icity o f the cocaine. In spite o f this
development, however, untoward symp­
toms continued to be of such frequency
that a compound having the local anes­
thetic properties o f cocaine was sought.
In 1905, Einhorn succeeded in synthesiz­
ing procaine (novocaine). Here was a
drug having the anesthetic properties of
cocaine, with about one-seventh its tox­
icity. Unfortunately, procaine had one
serious drawback in that it had no con­
stricting effect on the blood vessels such
as occurs with cocaine. It became neces­
sary, therefore, to add a vasoconstrictor
to further increase the margin of safety
of procaine and to make it as effective a
local anesthetic from the standpoint of
T a b l e 4 .— F r o g H e a r t P e r f u s i o n
Cocaine
Procaine
Alypin
duration as cocaine. T he addition of
epinephrine accomplished this purpose,
but the solution is still short o f being the
ideal anesthetic agent.
A n ideal anesthetic solution should be
sterile, and it should be capable o f pro­
ducing profound anesthesia, rapid in ac­
tion, and of sufficient duration to permit
the usual dental operative procedures,
with the minimum o f undesirable after­
effects. It should contain a vasoconstrict-
ing agent that does not cause unfavorable
symptoms or elicit toxic reactions when
properly administered, and it should con­
form as nearly as possible to the physio­
logic laws and functions o f the living cells.
A general survey o f experimental stud­
ies that have been made in connection
with the various local anesthetic and vaso-
constricting compounds in an effort to
find an ideal local anesthetic solution will
permit a better understanding and proper
evaluation o f facts available at the pres­
ent time.
ANALYSIS OF EXPERIMENTAL STUDIES IN
CONNECTION WITH LOCAL ANESTHETIC
AGENTS
The accepted methods for determining
the concentration per cent, efficiency
ratio, toxicity and duration of action of
local anesthetic solutions, are by :
1. N erve block; e.g., standard frog sci­
atic nerve method.
2. Efficiency on mucous membrane,
and on the human cornea and the rabbit
cornea.
3. Injection efficiency, by the standard
wheal test on man.
4. Toxicity, by subcutaneous and vein
administration on guinea-pigs, rats, cats
and dogs, which also furnishes an index
on respiration, heart action and circula­
tion.
In m aking a survey of local anesthetic
agents that have been used clinically,
some more extensively than others, a com­
100 parison as to their local effects, tolerated
6
dosages, systemic toxicities and therapeu­
210
tic margins o f safety has been made in
Tables 1, 2, 3 and 4.
These data indicate the fallacy o f eval­
uating the anesthetic efficiency o f a prod­
uct on the basis of one test only. T h e
broad field of usefulness can be deter­
mined only by noting the efficiency under
varying conditions, thus taking into ac­
count the variability as to absorption. The
final analysis, in any case, must be gov­
erned by the margin of safety or the
ratio between the effective and the mini­
mal toxic dose. For general usefulness,
combining the maximal efficiency and
minimal toxicity, procaine is easily the
local anesthetic o f choice today as in 1905.
EVALUATION OF VASOCONSTRICTOR COM­
POUNDS OF IMPORTANCE TO LOCAL
ANESTHESIA
T h e practical usefulness o f any local
anesthetic depends primarily on the abo­
lition or the blocking o f sensory impulses
from the field o f operation. In order to
accomplish this with the local anesthetic
agents available today, the addition o f a
M iller— Local Anesthetics and. Vasoconstrictors 395

vasoconstrictor in some form is necessary be classified as Group I : Pyrocatechin

to prolong anesthesia and to lessen the
tendency toward toxic reactions due to
too rapid absorption of the injected solu­
tion, thus facilitating dental operative
procedures and eliminating as far as pos­
sible any systemic effects due to mass
absorption of the local anesthetic injected.
derivatives: epinephrine and arterenol;
Group I I : Benzol derivatives: ephedrine,
cobefrin and benzedrine, and Group I I I :
Phenol derivatives: synephrin and neo-
synephrin.
The practical usefulness o f such vaso­
constrictors is best illustrated in Table 5,

T a b l e 5 .— I n f l u e n c e o f S e r i e s o f V a s o c o n s t r i c t o r C o m p o u n d s
on S u b c u t a n e o u s T o x ic it y o f St r y c h n in e in M ic e *

Medication (Subcutaneous) Concentration Minimum Ratio of Strychnine Reactions

of Vasocon­ Lethal Toxicity to Ten Mice per Group
strictor Dose in Epinephrine
Administered M g./Kg. as Unity
Per Cent Survived Killed

Strychnine — — — 0 10
Strychnine + adrenalin HC1 1 5 1.0 6 4
Strychnine + cobefrin HC1 1 30 0 .1 -0 .1 6 8 2
Strychnine + stryphnon HC1 50 750 0.0066 9 1
Strychnine + synephrin Tnt. 50 1250 0.004 7 3
Strychnine + neosynephrin HC1 10 125 0.04 6 4
Strychnine + ephedrine HC1 50 500 0.01 8 2
Strychnine + ephetonine HC1 50 500 0.01 9 1
Controls received 2.13 mg. of strychnine (subcutaneously) per kilogram. All treated animals received
strychnine in the same dose as the controls, plus the vasoconstrictors in a single injection at one site.
*H. Rotter, 1936.

T a b l e 6 .— R e l a t iv e T o x ic it ie s

Compound M .L.D . Ratio of Oral M.L.D. Ratio between

[ Intravenous Toxicity Mg. per Kg. Oral and Vein
Mg. per Kg. (Epinephrine = 1) Toxicity
Oral Toxicity

Vein Toxicity

Epinephrine HC1 0.1 1 SO 500

Cobefrin HC1 1.0 0.1 200 200
Ephedrine HC1 70.0 0.0014 400 5.7

A study of the relative effects of a series of vasoconstrictor agents on intravenous administration to

cats indicates, on the basis of dosages, the following order from greatest to least: epinephrine (1);
arterenol (1.2); cobefrin (3 to 6); neosynephrin, ephedrine (350); benzedrine (425).

T h e prolongation of anesthesia and which shows the limiting effects of vaso­

the m aximal limitation of systemic toxic­
ities of local anesthetic compounds is
best accomplished by the combined use
o f an anesthetic agent with the maximal
efficiency and greatest margin of safety
and a vasoconstrictor o f the epinephrine
type. T he more important of these com­
pounds, from a clinical standpoint, may
constrictor compounds on the absorption
o f lethal dosages of strychnine adminis­
tered subcutaneously to mice.
T he relative toxicities o f three well-
known hypertensive compounds following
oral and vein administration in rats are
illustrated in T able 6.
T h e practical importance of a com­
396 T h e Journal of the American Dental Association and T h e Dental Cosmos
pound which combines a moderate local
vasoconstrictor effect with a proportion­
ately smaller systemic effect on absorption
is emphasized by our clinical observations
on procaine solutions in combination with
epinephrine in varying concentration, and
cobefrin hydrochloride, reports o f which
have previously been published.7
C O N C L U S IO N S
The accumulated information in regard
to experimental and clinical experiences
with local anesthetic solutions and their
reactions in relation to tissues, and an
evaluation o f local anesthetics and vaso­
constrictor agents, are presented with the
object of clarifying certain points in re­
lation to the nature, efficiency and modes
o f action o f preparations in general use
in the field of clinical dentistry. T h e re­
sults appear to indicate th a t:
1. Procaine (novocaine) is the most
effective and safest local anesthetic agent
available at the present time.
2. A ll local anesthetic compounds avail­
able at present must be combined with a
vasoconstrictor in some form in order to
avoid toxic reaction due to too rapid ab­
sorption and to prolong anesthesia for a
sufficient length of time.
3. O f the available vasoconstrictors,
epinephrine, cobefrin and neosynephrin
seem to be the most desirable for dental
operations.
4. Weaker concentrations o f epineph­
rine in combination with procaine will
produce less pronounced change in blood
pressure, pulse rate and the tendency to
disturbing clinical reactions. T he epi­
nephrine content should not exceed 1 :50,-
000 concentration.
5. T h e use o f cobefrin hydrochloride in
sufficient concentrations to prolong anes­
thesia for dental operative procedures
gives rise to even less change in blood
pressure and pulse rate and produces
fewer undesirable clinical reactions.
6. Neosynephrin in combination with a
local anesthetic has not had extensive use
in dentistry, although several have re­
ported favorably on its action.
7. It is hoped that the material pre­
sented will broaden the general inform a­
tion of the dental profession; permit a
more critical viewpoint, a better under­
standing o f products in use and more
careful observations as to anesthesia, and,
perhaps, result in further advances of
practical benefit to the patient and to the
practitioner.
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