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Experimental and clinical evaluation of unacaine hydrochloride as a local anesthetic agent
Research EXPERIMENTAL AND CLINICAL EVALUATION OF UNACAINE HYDROCHLORIDE AS A LOCAL ANESTHETIC AGENT _____ MARSHALL I.
NEVIN, M.D., ELIAS EPSTKI~T, M.S., BND HILLARD R. NEVIN, D.D.S., BROOKLIT,
N. T;.
the discovery of cocaine’s local anesthetic properties, more potent SINCE less toxic local anesthetic drugs have been sought, The synthesis of
and pro-
caine in 1905 was a, distinct step forward, but progress in the field has since been slower than most investigators had hoped, While Monocaine, synthesized in 1936, was found to be more potent t,han procaine and within its toxic range, most of the other local anesthetics that have been prepared have shown no particular advantage over procaine. Several long-acting local anesthetics have been synthesized within recent years but these are all more toxic than procaine, and it has been demonstrated’ that they act, in pa,rt, by producing neural irritation. It would seem, therefore, that their use is potentially hazardous in this regard. We have recently investigated one of a promising group of meta-amino benzoate esters and have found a marked decrease in the subcutaneous toxicity of the drug, without the expected decrease in its anesthetic potency. This compound, Unacaine Hydrochloride (2-isobutylaminoethyl meta-aminobenzoate hydrochloride), is a white crystalline salt, melting at 181° to 183’ C. It is soluble in distilled water to the extent of 6 per cent at 0’ C., 10 per cent at 25O C., and 14 per cent at 40° C. It is 1.4 per cent soluble in 95 per cent ethyl alcohol and slightly soluble in isopropyl alcohol, acetone, ether, and chloroform. The structural formula of Unacaine Hydrochloride is : COO CH, CH, NHC, H,
@NH2
I,/
>1
Toxicity In evaluating the toxic dose of Unacaine, the LD,, was determined by subcutaneous and intraperitoneal injection into white mice, and intravenous injection into rabbits and cats. When calculating the numerical value of LD,,, the statistical device of summating the animals dying and those living, and determining the point at which these two would cross if plotted as curves, was employed.2a 3 Subcutaneous LD,, in Mice,-Healthy white male Swiss mice of 12 tb 15 grams in weight were selected and observed for several days for normality of The mice were then injected, using a fine gauge needle, with the behavior. various doses of Unacaine. Solutions ranging from 4 per cent to 10 per cent were used, wit,h higher concentrations used for the higher doses to avoid 1228
leakage. If no wheal formed or if leakage was observed during or after the injection, t,he findings on that, animal were not included in the results. Animals which lived more than twenty-four hours after injection were considered to have survived. Table I shows the results of these tests. The LD,, of Unacaine was 3,670 mg./kg. Parallel studies on Monocaine and procaine, using the same strain of mice, resulted in an LD,,, for Monocaine of 420 mg.jkg. and for procaine of 640 mg./kg. These compare with literature figures of 449 mg./kg.” and ‘750 nlg./kg.,6 respectively. Thus, the subcutaneous toxicity of IJnacaine is calculated at less than one-fifth that, of Monocainr or procaine. TABIX II.
INTRAPERITONEAT. TOXICIT-V OP UNACAINE ON 8wiss
MAIX
~VHITP:
,MICW
group of whit,e male Swiss mice Intraperitoneal LD,, in Mice.-Another was injected intraperitoneally with 4 per cxent Unacaine solution, precautions heing taken to avoid leakage. As shown in Table II, the LD,, was found to be 644 mg./kg. by this method. Comparable toxicities appearing in the Iitrrat,ure of 203 mg./kg.” for Monocaine and 124 mg./kp.: for procaine iother investigators? give a higher LD,,, for procaine) indicate that intraperit,oneally linacaine is ahout one-third as toxic as MonocGnc, and one-fifth as toxic* as procaine.
Intravenous LD,, in Rabbits and Cats.-Intravenous LD,, was determined by injection of a 4 per cent aqueous solut,ion of Unacaine and Monocaine int-o both rahbits and cats. The injections were given into a suitable ear vein of the rabbit and the femoral rein of tbr cat. The substance was injected slowly, and if any extravasation occurred, the results in that animal were not used in the calculations. Table III shows the results of this procedure. The LD,, for Unacaine was 3% mg./kg. in rabbits and 31.5 mg./kg. in cats. This places Unacaine in the same range of intravenous toxicit,ies as Monocaine and procaine (35.1 mg./kg. and 30.9 mg./kg., respectivelgz) .
1230
NEVIN, TABLE
III.
EPSTEIN,
INTRAVENOUS 1
LIVED
NEVTN
TOXICITY
OF UNA('AINF I_x___ DIED 1 - JJVED Rabbits
-Pm----MG./KG.
AND
j
ON RABBITS (STJM.)
AKD CATS \
DIED
1 ‘> E 1 1 I;D,,
=
(SUM.)
-
1 4 i 10 35
mg./kg.
Cats
Ii
40
35 40
0 0
0
4 0 0 0
n
F 0 -__I_
LD, 2
31.5
mg./kg. -
Anesthetic Potency Anesthetic potency was evaluated by two methods, instillation of solution into the rabbit’s conjunctival sac, and sciatic nerve block in the intact guinea pig. Anesthetic Potency by Instillation Into Rabbit’s Eye.-This time-honored method of determination of anesthetic potency involves instillation of various concentrations of anesthetic agent into the rabbit’s conjunctival sac. Presence or absence of anesthesia is then determined by the status of the cornea1 reflex. This method is now considered to be defective in that the absorptive power through the cornea1 mucosa, as well as the potency of the anesthetic drug itself, governs the duration of anesthesia. Several concentrations of Unacaine and Monocaine were compared in this manner; the results are listed in Table IV. Unacaine was found to be less effective than Monocaine in inducing this type of anesthesia. TABLE
IV.
TOPICAL
ANXSTHESIA
ON CORNEA
OE RABBITS -
%
SOLUTION 2
I
AVERtlGE LENGTH WITH UNACAINE 26 20 11
ANESTHESIA (MINUTES)
1 1
AVERAGE LENGTH WITH MONOCAINE
ANESTHESIA (MINUTES)
46 38 28
Anesthetic Potency by the Sciatic Nerve Block in the Guinea Pig.-This method of determining anesthetic potency, introduced originally by ShackellY4 has the advantage of using an intact animal under conditions not unlike those in clinical practice. The method involves the placing of a constant volume of the solution to be tested (0.2 cc.) around the sciatic nerve by injecting into the bony furrow between the trochanter of the femur and the vertebral column. Anesthesia is evidenced by the disappearance of sensation in the area of the leg representing the sensory distribution of the sciatic nerve. The reader is referred to Shackell’s original work for a complete description of the procedure. To check the accuracy of Shackell’s landmarks we incorporated a small amount of methylene blue in several solutions and sacrificed the animal after blocking the sciatic nerve. The results obtained by this method are listed in Table V. It will be noted that Unaeaine gave anesthesia of longer
TABLE
%
V.
w vi M
NERVE
BLOCK IX GVIXEA PIGS
AVERAGE DURATION OF ANESTHESIA I MONOCAINE
I
SOT~UTION*
SCIATIC
UNACAINE
(XINCTES) PROCAISR
1 1 2 (with epinephrine 1: 50,000) Total number of animals, constant at 0.2 C.C.
-*~‘olun~c injected
held
21
duration than Monocaine at the same concentrations. Thus, 1 per ceut UnwCaine gave anesthesia lasting fifty-one minutes, 1 per cent Monocaine. forty minutes, and 1 per cent procaine, twenty-one minutes. Table VT summarizes the results of toxicity and potency observations on Ilnacaine. Monocaine, and procaine. TABLE
VI.
I Subcutaneous (White mire) *. u .‘=, : B
lntraprritoneal ( Whitcl mice)
Intravenous (Cat) _~--____-.--__ Corned (topical) 5 ( A%bit ) 2
g
Sciatic .t+ock
nerve 1% (Guinea pig) -..-__^-_
SUMMARY
OF TOXICITY
uNA(‘AINE
LJAI Relative value LD,o
Relative value LD,o Relative value Minutes Relative value Minutes Relative value
AND POTENCY MONOCAINE
j
I_-. I--.
-._
PROCAINF --
3,67; zmg./kg.
449 mg./kg. 1.7
730 mg./kg. 1
644 mg./kg. 0.2
203 mg./kg. 0.6
124 m&kg. 1
35.1 mg./kg. 31.5 mg./kg. 0.9 1 _-___--_-____-_--.-
.
30.9 nlg./k& 1 ~~-. -_
20 -
38.0 -
-
51 2.3
40.0 1 .R
213 7
Clinical Study Clinical observations on Unacaine as a dental local anesthetic, covering 3,667 case histories, indicate that this newer local anesthetic differs considerably from procaine and Monocaine in respect to its induction time, intensity, and duration. While toxicity findings are somewhat difficult to evaluate on a clinical basis, investigators report that the incidence of unpleasant postinjection reactions appears to be much lower than those usually associated with procaine. Nausea, perspiration, pallor, trepidation, and fainting are usually ceonsideredto be signs of mild toxicity. Induction Time.-Clinical records indicate that Unacaine solutions of 15 mg. per cubic centimeter produce anesthesia more rapidly than those containing 20 mg. per cubic centimeter of Monocaine. In higher concentrations, however, Unacaine exhibits a marked advantage in induction time over procaine and Mouocaine. Unacaine solutions of 20, 30, 38, and 40 mg. per cubic centimeter provided a much shorter onset period than 2 per cent or 4 per cent pro-
1232
NEVIN,
EPSTEIN,
AND
NEVIN
Caine, or 2 per cent Monocaine solutions. While the results with 80 mg. per cubic centimeter of Unacaine with epinephrine 1 :lOO,OOOindicated adequate anesthetic depth and low toxicity, it was found that duration of anesthesia was relatively short. Infiltration anesthesia with all Unacaine solutions, from 20 mg. per cubic centimeter to 40 mg. per cubic centimeter, was almost instantaneous. The operator was able to begin his work as soon as the needle was removed from the tissues. Symptoms of mandibular and infraorbital anesthesia would frequently appear in thirty seconds, and complete surgical anesthesia was frequently obtained in ninety to one hundred twenty seconds. Intensity of Anesthesia.-From clinical reports, Unacaine appears to maintain anesthesia at maximum intensity for an average of ninety minutes, while procaine anesthesia seems to reach the peak of its intensity short,ly after injection and then drops until the solution is eliminated from the tissues. Unacaine anesthesia seems to maintain a deep level of intensity for well over an hour, and when anesthesia disappears, it goes quite rapidly. A number of patients have remarked that anesthesia was present at one moment and gone the next. Symptoms of anesthesia with Unacaine are closely related to those of Monocaine and procaine, with the characteristic “t,ingling” OK “pins and needles” feeling during the initial stages and, in some cases, at the time when anesthesia is dissipated. Duration of Anesthesia.-Anesthetic duration is usually proportional to potency, but Unacaine seems to be an exception to this rule. A number of local anesthetics used in dentistry will frequently the so-called “strong” maintain anesthesia for a period of four to eight hours after the injection. Unacaine, on the other hand, provides a shorter duration, averaging about one hundred two minutes in the 38 mg. per cubic centimeter Supranol 1:60,000 concentration (see Table VII). The 38 mg. per cubic centimeter Supranol l:100,000 dilution provides an average duration of sixty-five minutes. TABLE TYPE
VII.
LENGTH
OF OPERATlON
Extraction and Surgery Cavity preparation and pulp Extirpation - -
OF ANESTHESIA TYPE
(4 PER CENT UNACAINE HCl-1:50,000
OF INJECTION
Infiltration nerve block Infiltration nerve block Summarv
AVERAGE LENGTH ANESTHESIA
NUMBER OF INJECTIONS
38 55 68 44 205
EPINEPHRINE)
A
105 105 95 105
OF
min. min. min. min.
102 min.
While Unacaine’s shorter duration may occasionally necessitate a second injection, most research workers in the field feel that this shorter duration is of marked advantage in the average case. It has been shown that the ideal local anesthetic should cover the operative period and then disappear. Prolongation beyond this period is more likely to interfere with the tissue functions’ and may, in some cases, endanger their vitality. Certainly, for dental purposes, the most desirable local anesthetic is one which permits intense anesthesia during the operative period only, and is then dissipated as soon as possible upon completion of the operation.
UNACBINE
HYDROCHLORIDE
AS
LOCAL
I-‘:;::
ANESTHETIC
Toxicity.-As previously mentioned, it is difficult to evaluate local anes thetic toxicity on a clinical basis since psychic disturbances will sometimes simulate toxic manifestations. While animal evaluations have provided iI quantitat,ive evaluation of Unacaine’s safety, clinical observations can. at best, be considered only as a qualitative measurerrlent. Nevertheless. it is nlost interesting to note that in 2,556 cases of the highest concentrations nr~~lyzrd. T’nacaine was listed as nontosic in 97.5 per cent. There were no reports oi severe toxic manifestations. Only 2.5 ])er cent were classified a,s “mildI> toxic,” and this group included fainting, nausea, pallor, ant1 perspiration, ail of possible psychic origin. 111many cases the clinical observer stated in his report that the mild toxic reaction which occurred did not appear to he produced by the anesthetic> per se. Only O.‘i per cent of all injections of the highest concentrations gave :~II~ indicat,ion off postinjection complications such as pain, sloughing. and (1r.v sockets. Surgical cases included simple extractions, the removal of impacted teeth. alveolectomies, cyst enucleations, apicoectomies, and surgery of the soft tissues. I’ndcr the classification cavity preparation and pulp extirpation, a fairly high percentage of jacket-crown and root canal therapy was performed. TABLE --.___
ASESTIIETIC
FORMIJLA: EXTRACTION
/ INFII,TRATION
Number of injections Anesthesia Profound Fair Poor Toxicity Normal Mild Severe Postinjection Normal Abnormal
\rIII.
CLINICAL
&JMMARY
_.___ ~._..~._ . I'NACAINE HCI-EPINEPHRINE I:fiO,OOO CAVITY PREPARATION AND ) PT:LP EXTIRPATION I STWMAKY AND SURGERY (IN IKFII,TRATION / PI‘ERVE BLOCKS PER cFx1‘) , NERVE RLOCKS 38 MG./c.c~.
-----.--.-
- .
828
1,010
414
304
798 29 1
964 41 5
388 23 2
273 23 8
94.8 4.5
so7 21 0
984 26 0
406 8 0
294 10 0
97.5 2.5 0
823 5
1,005 5
410 4
300 4
99.3 0.7
0.7
Penicillin Compatibility.-Unacaine, like Monocaine but unlike procaine, does not form an insoluble penicillin salt. Therefore, Unacaine-penicillin solutions may be used for simultaneous administration of the antibiotic and anesthetic. Surgical anesthesia will follow the Unacaine-penicillin injection. and a high local penicillin level will be maintained as long as the Supranol content of the solution prevents absorption, Following the dissipation of anesthesia. a seconda.ry penicillin blood level is established. Dermal Sensitivity.-Preliminary studjes on procaine-sensitive individuals suggest t.hat Unacaine may not produce dermatitis. For some time research workers have felt that the para-aminobenzoic acid portion of the local anesthetic molecule was responsible for the production of dermatit,is. Since Llua-
1234
NEVIN,
EPSTEIN,
AND NEVIN
Caine is a meta-aminobenzoic acid derivative, it may be found to be nonirritating to individuals who have been sensitized to procaine. A limited study, in which Unacaine produced negative skin tests in a number of procaine-sensitive individuals, is encouraging, but additional work will have to be done before definite conclusions may be drawn. Conclusions Unacaine Hydrochloride is a safe, efficient local anesthetic possessing a number of advantages over procaine. 1. On subcutaneous injection it is approximately five times safer than procaine on a gram-for-gram basis. In clinical concentrations (38 mg. per cubic centimeter) it is about two and one-half times safer than a procaine 2 per cent solution when injected subcutaneously. 2. Unacaine is at least twice as potent as procaine on a gram-for-gram basis. 3. Since Unacaine has no intravenous toxicity advantages over procaine, it is quite likely that its low subcutaneous toxicity indicates that it is partially detoxified in the tissue fluids. 4. Unacaine anesthesia is established almost immediately after injection and is maintained at maximum intensity for about one to one and one-half hours, after which it abruptly leaves. Procaine, on the other hand, appears to require more time to establish anesthesia following the injection, and its anesthesia plane then seems to begin to taper off until anesthesia gradually disappears. 5. There is some evidence to indicate that Unacaine is less likely than procaine to produce allergic reaction and dermatitis, and this is probably because of the meta position of the amino group on its benzene ring. 6. The incidence of mildly toxic symptoms with Unacaine is very low, with no report of a single case of severe toxic manifestation in 3,667 case histories. 7. Clinical studies with Unacaine show an extremely low incidence of any postinjection complications. 8. Unacaine, like Monocaine, but unlike procaine, is compatible with penicillin and does not precipitate and form the penicillinate salt when used as the solvent for crystalline sodium penicillin.
References 1. Co Tui, Preiss, A. L., Bareham! I., and Nevin, M. I.: Local Nervous Tissue Changes Following Spinal Anesthesia in Experimental Animals, J. Pharm. & Expel. Therap. 81: July 1944. An Approximate Method of Determining Median 2. Irwin, J. O., and Cheeseman, E. A.: Effective Dose and Its Error in Case of Quanta1 Response, J. Hygiene 39: 374-580, 1939. Determination of Dosage-Mortality Curve From Small Numbers, Quart. J. 3. Bliss, C. I.: Pharm. & Pharmacol. 11: 192-216, 1938. Tests of Local Anesthetics by Sciatic Nerve Block in the Intact Guinea 4. Shackell, L. F.: Pig, Anesth. & Analg. 14: 1, 1935. Pharmacological Effects of Mono5. Schamp, J. R., Schamp, H. M., and Tainter, M. L.: caine HCl, Anesthesiology 3: 398-414, 1942. Experimental Toxicity and Effectiveness 6. Co Tui, Preiss, A., Nevin, M., and Barcham, I.: of Octocaine as a Local Anesthetic Agent, Anesth. & Analg. 22: 301-312, 1943. Comparative Toxicity and Potency of Standard Commercial 7. Epstein, E., and Silver, D.: Monocains and Procaine Solutions, Anesth. & Analg. 24: 38-42, 1945.
NEVIN, M.D., ELIAS EPSTKI~T, M.S., BND HILLARD R. NEVIN, D.D.S., BROOKLIT,
N. T;.
the discovery of cocaine’s local anesthetic properties, more potent SINCE less toxic local anesthetic drugs have been sought, The synthesis of
and pro-
caine in 1905 was a, distinct step forward, but progress in the field has since been slower than most investigators had hoped, While Monocaine, synthesized in 1936, was found to be more potent t,han procaine and within its toxic range, most of the other local anesthetics that have been prepared have shown no particular advantage over procaine. Several long-acting local anesthetics have been synthesized within recent years but these are all more toxic than procaine, and it has been demonstrated’ that they act, in pa,rt, by producing neural irritation. It would seem, therefore, that their use is potentially hazardous in this regard. We have recently investigated one of a promising group of meta-amino benzoate esters and have found a marked decrease in the subcutaneous toxicity of the drug, without the expected decrease in its anesthetic potency. This compound, Unacaine Hydrochloride (2-isobutylaminoethyl meta-aminobenzoate hydrochloride), is a white crystalline salt, melting at 181° to 183’ C. It is soluble in distilled water to the extent of 6 per cent at 0’ C., 10 per cent at 25O C., and 14 per cent at 40° C. It is 1.4 per cent soluble in 95 per cent ethyl alcohol and slightly soluble in isopropyl alcohol, acetone, ether, and chloroform. The structural formula of Unacaine Hydrochloride is : COO CH, CH, NHC, H,
@NH2
I,/
>1
Toxicity In evaluating the toxic dose of Unacaine, the LD,, was determined by subcutaneous and intraperitoneal injection into white mice, and intravenous injection into rabbits and cats. When calculating the numerical value of LD,,, the statistical device of summating the animals dying and those living, and determining the point at which these two would cross if plotted as curves, was employed.2a 3 Subcutaneous LD,, in Mice,-Healthy white male Swiss mice of 12 tb 15 grams in weight were selected and observed for several days for normality of The mice were then injected, using a fine gauge needle, with the behavior. various doses of Unacaine. Solutions ranging from 4 per cent to 10 per cent were used, wit,h higher concentrations used for the higher doses to avoid 1228
leakage. If no wheal formed or if leakage was observed during or after the injection, t,he findings on that, animal were not included in the results. Animals which lived more than twenty-four hours after injection were considered to have survived. Table I shows the results of these tests. The LD,, of Unacaine was 3,670 mg./kg. Parallel studies on Monocaine and procaine, using the same strain of mice, resulted in an LD,,, for Monocaine of 420 mg.jkg. and for procaine of 640 mg./kg. These compare with literature figures of 449 mg./kg.” and ‘750 nlg./kg.,6 respectively. Thus, the subcutaneous toxicity of IJnacaine is calculated at less than one-fifth that, of Monocainr or procaine. TABIX II.
INTRAPERITONEAT. TOXICIT-V OP UNACAINE ON 8wiss
MAIX
~VHITP:
,MICW
group of whit,e male Swiss mice Intraperitoneal LD,, in Mice.-Another was injected intraperitoneally with 4 per cxent Unacaine solution, precautions heing taken to avoid leakage. As shown in Table II, the LD,, was found to be 644 mg./kg. by this method. Comparable toxicities appearing in the Iitrrat,ure of 203 mg./kg.” for Monocaine and 124 mg./kp.: for procaine iother investigators? give a higher LD,,, for procaine) indicate that intraperit,oneally linacaine is ahout one-third as toxic as MonocGnc, and one-fifth as toxic* as procaine.
Intravenous LD,, in Rabbits and Cats.-Intravenous LD,, was determined by injection of a 4 per cent aqueous solut,ion of Unacaine and Monocaine int-o both rahbits and cats. The injections were given into a suitable ear vein of the rabbit and the femoral rein of tbr cat. The substance was injected slowly, and if any extravasation occurred, the results in that animal were not used in the calculations. Table III shows the results of this procedure. The LD,, for Unacaine was 3% mg./kg. in rabbits and 31.5 mg./kg. in cats. This places Unacaine in the same range of intravenous toxicit,ies as Monocaine and procaine (35.1 mg./kg. and 30.9 mg./kg., respectivelgz) .
1230
NEVIN, TABLE
III.
EPSTEIN,
INTRAVENOUS 1
LIVED
NEVTN
TOXICITY
OF UNA('AINF I_x___ DIED 1 - JJVED Rabbits
-Pm----MG./KG.
AND
j
ON RABBITS (STJM.)
AKD CATS \
DIED
1 ‘> E 1 1 I;D,,
=
(SUM.)
-
1 4 i 10 35
mg./kg.
Cats
Ii
40
35 40
0 0
0
4 0 0 0
n
F 0 -__I_
LD, 2
31.5
mg./kg. -
Anesthetic Potency Anesthetic potency was evaluated by two methods, instillation of solution into the rabbit’s conjunctival sac, and sciatic nerve block in the intact guinea pig. Anesthetic Potency by Instillation Into Rabbit’s Eye.-This time-honored method of determination of anesthetic potency involves instillation of various concentrations of anesthetic agent into the rabbit’s conjunctival sac. Presence or absence of anesthesia is then determined by the status of the cornea1 reflex. This method is now considered to be defective in that the absorptive power through the cornea1 mucosa, as well as the potency of the anesthetic drug itself, governs the duration of anesthesia. Several concentrations of Unacaine and Monocaine were compared in this manner; the results are listed in Table IV. Unacaine was found to be less effective than Monocaine in inducing this type of anesthesia. TABLE
IV.
TOPICAL
ANXSTHESIA
ON CORNEA
OE RABBITS -
%
SOLUTION 2
I
AVERtlGE LENGTH WITH UNACAINE 26 20 11
ANESTHESIA (MINUTES)
1 1
AVERAGE LENGTH WITH MONOCAINE
ANESTHESIA (MINUTES)
46 38 28
Anesthetic Potency by the Sciatic Nerve Block in the Guinea Pig.-This method of determining anesthetic potency, introduced originally by ShackellY4 has the advantage of using an intact animal under conditions not unlike those in clinical practice. The method involves the placing of a constant volume of the solution to be tested (0.2 cc.) around the sciatic nerve by injecting into the bony furrow between the trochanter of the femur and the vertebral column. Anesthesia is evidenced by the disappearance of sensation in the area of the leg representing the sensory distribution of the sciatic nerve. The reader is referred to Shackell’s original work for a complete description of the procedure. To check the accuracy of Shackell’s landmarks we incorporated a small amount of methylene blue in several solutions and sacrificed the animal after blocking the sciatic nerve. The results obtained by this method are listed in Table V. It will be noted that Unaeaine gave anesthesia of longer
TABLE
%
V.
w vi M
NERVE
BLOCK IX GVIXEA PIGS
AVERAGE DURATION OF ANESTHESIA I MONOCAINE
I
SOT~UTION*
SCIATIC
UNACAINE
(XINCTES) PROCAISR
1 1 2 (with epinephrine 1: 50,000) Total number of animals, constant at 0.2 C.C.
-*~‘olun~c injected
held
21
duration than Monocaine at the same concentrations. Thus, 1 per ceut UnwCaine gave anesthesia lasting fifty-one minutes, 1 per cent Monocaine. forty minutes, and 1 per cent procaine, twenty-one minutes. Table VT summarizes the results of toxicity and potency observations on Ilnacaine. Monocaine, and procaine. TABLE
VI.
I Subcutaneous (White mire) *. u .‘=, : B
lntraprritoneal ( Whitcl mice)
Intravenous (Cat) _~--____-.--__ Corned (topical) 5 ( A%bit ) 2
g
Sciatic .t+ock
nerve 1% (Guinea pig) -..-__^-_
SUMMARY
OF TOXICITY
uNA(‘AINE
LJAI Relative value LD,o
Relative value LD,o Relative value Minutes Relative value Minutes Relative value
AND POTENCY MONOCAINE
j
I_-. I--.
-._
PROCAINF --
3,67; zmg./kg.
449 mg./kg. 1.7
730 mg./kg. 1
644 mg./kg. 0.2
203 mg./kg. 0.6
124 m&kg. 1
35.1 mg./kg. 31.5 mg./kg. 0.9 1 _-___--_-____-_--.-
.
30.9 nlg./k& 1 ~~-. -_
20 -
38.0 -
-
51 2.3
40.0 1 .R
213 7
Clinical Study Clinical observations on Unacaine as a dental local anesthetic, covering 3,667 case histories, indicate that this newer local anesthetic differs considerably from procaine and Monocaine in respect to its induction time, intensity, and duration. While toxicity findings are somewhat difficult to evaluate on a clinical basis, investigators report that the incidence of unpleasant postinjection reactions appears to be much lower than those usually associated with procaine. Nausea, perspiration, pallor, trepidation, and fainting are usually ceonsideredto be signs of mild toxicity. Induction Time.-Clinical records indicate that Unacaine solutions of 15 mg. per cubic centimeter produce anesthesia more rapidly than those containing 20 mg. per cubic centimeter of Monocaine. In higher concentrations, however, Unacaine exhibits a marked advantage in induction time over procaine and Mouocaine. Unacaine solutions of 20, 30, 38, and 40 mg. per cubic centimeter provided a much shorter onset period than 2 per cent or 4 per cent pro-
1232
NEVIN,
EPSTEIN,
AND
NEVIN
Caine, or 2 per cent Monocaine solutions. While the results with 80 mg. per cubic centimeter of Unacaine with epinephrine 1 :lOO,OOOindicated adequate anesthetic depth and low toxicity, it was found that duration of anesthesia was relatively short. Infiltration anesthesia with all Unacaine solutions, from 20 mg. per cubic centimeter to 40 mg. per cubic centimeter, was almost instantaneous. The operator was able to begin his work as soon as the needle was removed from the tissues. Symptoms of mandibular and infraorbital anesthesia would frequently appear in thirty seconds, and complete surgical anesthesia was frequently obtained in ninety to one hundred twenty seconds. Intensity of Anesthesia.-From clinical reports, Unacaine appears to maintain anesthesia at maximum intensity for an average of ninety minutes, while procaine anesthesia seems to reach the peak of its intensity short,ly after injection and then drops until the solution is eliminated from the tissues. Unacaine anesthesia seems to maintain a deep level of intensity for well over an hour, and when anesthesia disappears, it goes quite rapidly. A number of patients have remarked that anesthesia was present at one moment and gone the next. Symptoms of anesthesia with Unacaine are closely related to those of Monocaine and procaine, with the characteristic “t,ingling” OK “pins and needles” feeling during the initial stages and, in some cases, at the time when anesthesia is dissipated. Duration of Anesthesia.-Anesthetic duration is usually proportional to potency, but Unacaine seems to be an exception to this rule. A number of local anesthetics used in dentistry will frequently the so-called “strong” maintain anesthesia for a period of four to eight hours after the injection. Unacaine, on the other hand, provides a shorter duration, averaging about one hundred two minutes in the 38 mg. per cubic centimeter Supranol 1:60,000 concentration (see Table VII). The 38 mg. per cubic centimeter Supranol l:100,000 dilution provides an average duration of sixty-five minutes. TABLE TYPE
VII.
LENGTH
OF OPERATlON
Extraction and Surgery Cavity preparation and pulp Extirpation - -
OF ANESTHESIA TYPE
(4 PER CENT UNACAINE HCl-1:50,000
OF INJECTION
Infiltration nerve block Infiltration nerve block Summarv
AVERAGE LENGTH ANESTHESIA
NUMBER OF INJECTIONS
38 55 68 44 205
EPINEPHRINE)
A
105 105 95 105
OF
min. min. min. min.
102 min.
While Unacaine’s shorter duration may occasionally necessitate a second injection, most research workers in the field feel that this shorter duration is of marked advantage in the average case. It has been shown that the ideal local anesthetic should cover the operative period and then disappear. Prolongation beyond this period is more likely to interfere with the tissue functions’ and may, in some cases, endanger their vitality. Certainly, for dental purposes, the most desirable local anesthetic is one which permits intense anesthesia during the operative period only, and is then dissipated as soon as possible upon completion of the operation.
UNACBINE
HYDROCHLORIDE
AS
LOCAL
I-‘:;::
ANESTHETIC
Toxicity.-As previously mentioned, it is difficult to evaluate local anes thetic toxicity on a clinical basis since psychic disturbances will sometimes simulate toxic manifestations. While animal evaluations have provided iI quantitat,ive evaluation of Unacaine’s safety, clinical observations can. at best, be considered only as a qualitative measurerrlent. Nevertheless. it is nlost interesting to note that in 2,556 cases of the highest concentrations nr~~lyzrd. T’nacaine was listed as nontosic in 97.5 per cent. There were no reports oi severe toxic manifestations. Only 2.5 ])er cent were classified a,s “mildI> toxic,” and this group included fainting, nausea, pallor, ant1 perspiration, ail of possible psychic origin. 111many cases the clinical observer stated in his report that the mild toxic reaction which occurred did not appear to he produced by the anesthetic> per se. Only O.‘i per cent of all injections of the highest concentrations gave :~II~ indicat,ion off postinjection complications such as pain, sloughing. and (1r.v sockets. Surgical cases included simple extractions, the removal of impacted teeth. alveolectomies, cyst enucleations, apicoectomies, and surgery of the soft tissues. I’ndcr the classification cavity preparation and pulp extirpation, a fairly high percentage of jacket-crown and root canal therapy was performed. TABLE --.___
ASESTIIETIC
FORMIJLA: EXTRACTION
/ INFII,TRATION
Number of injections Anesthesia Profound Fair Poor Toxicity Normal Mild Severe Postinjection Normal Abnormal
\rIII.
CLINICAL
&JMMARY
_.___ ~._..~._ . I'NACAINE HCI-EPINEPHRINE I:fiO,OOO CAVITY PREPARATION AND ) PT:LP EXTIRPATION I STWMAKY AND SURGERY (IN IKFII,TRATION / PI‘ERVE BLOCKS PER cFx1‘) , NERVE RLOCKS 38 MG./c.c~.
-----.--.-
- .
828
1,010
414
304
798 29 1
964 41 5
388 23 2
273 23 8
94.8 4.5
so7 21 0
984 26 0
406 8 0
294 10 0
97.5 2.5 0
823 5
1,005 5
410 4
300 4
99.3 0.7
0.7
Penicillin Compatibility.-Unacaine, like Monocaine but unlike procaine, does not form an insoluble penicillin salt. Therefore, Unacaine-penicillin solutions may be used for simultaneous administration of the antibiotic and anesthetic. Surgical anesthesia will follow the Unacaine-penicillin injection. and a high local penicillin level will be maintained as long as the Supranol content of the solution prevents absorption, Following the dissipation of anesthesia. a seconda.ry penicillin blood level is established. Dermal Sensitivity.-Preliminary studjes on procaine-sensitive individuals suggest t.hat Unacaine may not produce dermatitis. For some time research workers have felt that the para-aminobenzoic acid portion of the local anesthetic molecule was responsible for the production of dermatit,is. Since Llua-
1234
NEVIN,
EPSTEIN,
AND NEVIN
Caine is a meta-aminobenzoic acid derivative, it may be found to be nonirritating to individuals who have been sensitized to procaine. A limited study, in which Unacaine produced negative skin tests in a number of procaine-sensitive individuals, is encouraging, but additional work will have to be done before definite conclusions may be drawn. Conclusions Unacaine Hydrochloride is a safe, efficient local anesthetic possessing a number of advantages over procaine. 1. On subcutaneous injection it is approximately five times safer than procaine on a gram-for-gram basis. In clinical concentrations (38 mg. per cubic centimeter) it is about two and one-half times safer than a procaine 2 per cent solution when injected subcutaneously. 2. Unacaine is at least twice as potent as procaine on a gram-for-gram basis. 3. Since Unacaine has no intravenous toxicity advantages over procaine, it is quite likely that its low subcutaneous toxicity indicates that it is partially detoxified in the tissue fluids. 4. Unacaine anesthesia is established almost immediately after injection and is maintained at maximum intensity for about one to one and one-half hours, after which it abruptly leaves. Procaine, on the other hand, appears to require more time to establish anesthesia following the injection, and its anesthesia plane then seems to begin to taper off until anesthesia gradually disappears. 5. There is some evidence to indicate that Unacaine is less likely than procaine to produce allergic reaction and dermatitis, and this is probably because of the meta position of the amino group on its benzene ring. 6. The incidence of mildly toxic symptoms with Unacaine is very low, with no report of a single case of severe toxic manifestation in 3,667 case histories. 7. Clinical studies with Unacaine show an extremely low incidence of any postinjection complications. 8. Unacaine, like Monocaine, but unlike procaine, is compatible with penicillin and does not precipitate and form the penicillinate salt when used as the solvent for crystalline sodium penicillin.
References 1. Co Tui, Preiss, A. L., Bareham! I., and Nevin, M. I.: Local Nervous Tissue Changes Following Spinal Anesthesia in Experimental Animals, J. Pharm. & Expel. Therap. 81: July 1944. An Approximate Method of Determining Median 2. Irwin, J. O., and Cheeseman, E. A.: Effective Dose and Its Error in Case of Quanta1 Response, J. Hygiene 39: 374-580, 1939. Determination of Dosage-Mortality Curve From Small Numbers, Quart. J. 3. Bliss, C. I.: Pharm. & Pharmacol. 11: 192-216, 1938. Tests of Local Anesthetics by Sciatic Nerve Block in the Intact Guinea 4. Shackell, L. F.: Pig, Anesth. & Analg. 14: 1, 1935. Pharmacological Effects of Mono5. Schamp, J. R., Schamp, H. M., and Tainter, M. L.: caine HCl, Anesthesiology 3: 398-414, 1942. Experimental Toxicity and Effectiveness 6. Co Tui, Preiss, A., Nevin, M., and Barcham, I.: of Octocaine as a Local Anesthetic Agent, Anesth. & Analg. 22: 301-312, 1943. Comparative Toxicity and Potency of Standard Commercial 7. Epstein, E., and Silver, D.: Monocains and Procaine Solutions, Anesth. & Analg. 24: 38-42, 1945.