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A new local anesthetic agent: preliminary report
A new local anesthetic agent : preliminary report
Leonard. M . Monheim, D.D.S., Pittsburgh
A. new local anesthetic agent has been used for approximately a year in the clinic of the University of Pittsburgh School of Dentistry in order to determine its effectiveness for dental operative and surgical procedures when administered by block and infiltration technics. Chemically known as 2' diethylaminoethyl-2-butoxy-3-aminobenzoate hydro chloride, and issued under the brand name Primacaine HC1, the anesthetic is represented by this structural formula:
It was synthesized by Epstein and Myer.1,2 Chemical and physical proper ties and pharmacological data were de termined by the research department of Novocol Chemical Manufacturing Co., Inc. The new drug differs from local anes thetics of the butethamine and procaine types in that the amino group on the benzene ring is in the meta instead of the para position and a butoxy group is added to the ring’s 2 position. Primacaine HC1 occurs as a white crys tal with a melting point of 115° to 118° 633
C. It has a distilled water solubility of 75 per cent at room temperature and is stable to heat sterilization. Pharmacologically, Primacaine HC1 was found to have greater analgesic po tency than procaine, butethamine and metabutethamine, while subcutaneous and intraperitoneal toxicity studies place it in the procaine range. Because of its high analgesic potency, it may be used in a 1.5 per cent dilution while other anesthetic drugs are com monly furnished in 2 per cent and 4 per cent concentrations. The fact that clini cal testing with epinephrine dilutions of 1:200,000 and 1:400,000 indicated that these dilutions were sufficient to main tain anesthesia levels for periods of one to two hours suggests that the new anes thetic does not have vasodilator tenden cies. To determine whether excessive doses would produce systemic damage or local tissue irritation, two groups of rats re ceived daily injections of ten and 25
T h e m a t e r i a l u s e d in th is s tu d y w a s f u r n is h e d th r o u g h th e c o u r t e s y o f t h e N o v o c o l C h e m ic a l M a n u f a c t u r in g C o . , In c ., N e w Y o r k . F r o m th e d e p a r t m e n t o f a n e s th e s ia , U n iv e r s ity o f P it t s b u r g h S c h o o l o f D e n t is tr y . 1. E p s te in , E .; M y e r , M . , a n d G in s b e r g , H . E x p e r i m e n ts o f t o x i c i t y a n d lo c a l a n e s th e t ic a c t i v i t y o f a lk y / a m in o e th y l e s te rs o f m e ta a m in o a lk o x y b e n z o a te s . A c c e p t e d f o r p u b l i c a t i o n b y A n e s th e s ia a n d A n a l g e s ia R e s e a rc h J o u r n a l. 2 . E p s te in , E., a n d M y e r , M . M o n a a n d d i a lk y l a m in o e t h y l e s te rs o f m e ta a m in o a lk o x y b e n z o ic a c id s . U n p u b lis h e d .
634 • THE JO U R N A L O F T H E A M E R IC A N D EN T A L A S S O C IA T IO N
times the calculated human dose, and these animals were sacrificed at the end of a two week period for histological ex amination of the spleen, liver, kidneys and the muscle tissue at the injection sites. No variation was observed within the organs, blood counts were in the normal range, and the sites of the re peated daily injections showed no evi dence of irritation. The clinical studies at the University of Pittsburgh Dental School covered 470 injections on dental patients by the in filtration, mandibular, infraorbital and tuberosity methods. The cases in which it was used for surgical and for operative procedures were about equally divided. The Primacaine HC1 1.5 per cent solu tion was used with epinephrine dilutions which varied from 1:50,000 to 1:400,000; also included in the study were 20 injections of the 1.5 per cent solution without vasoconstrictor. The absence of a controlled study precluded a statistical evaluation at this time, but plans have been made to present a statistical com parison in a subsequent paper. DISCU SSIO N
All but one injection produced profound anesthesia, and the single instance which was classified as “fair anesthesia” followed the administration of the epinephrinefree solution. The group consisted of routine dental patients, taken as they presented themselves. None were selec tively excluded, but a number of indi viduals who had proved refractory to other anesthetic agents were included. Not a single anesthetic failure was en countered in the group of patients who had been refractory to other anesthetic drugs at previous appointments. The onset of local anesthesia was ex tremely rapid. In many instances it was estimated that surgical anesthesia was present within 30 to 45 seconds, while some patients volunteered the informa tion that they had experienced numb
ness before the needle had been with drawn. In practically every instance an esthesia was complete within a two minute period. Anesthesia duration was influenced by the vasoconstrictor concentration. In those instances in which the epinephrinefree solution was employed, duration ap proximated 30 minutes. The 1.5 per cent solution with epinephrine 1:50,000 gave a block anesthesia duration average some what in excess of three hours, while in filtration injections would last for 1f i to 2 hours. Epinephrine dilutions of 1:100,000, 1:125,000 and 1:150,000 produced anesthesia averages of about two hours. The epinephrine contents of 1:200,000 to 1:400,000 yielded proportionally briefer durations, but freer bleeding in the instances in which surgery was per formed was observed when the 1:400,000 solution was used. Because of the prolonged anesthesia and relatively minor incidence of toxicity, the optimum epi nephrine dilutions appear to be 1:50,000 and 1:125,000. Complications that arose during in jection or during the period of anesthesia were minor and few and, in most cases, could be attributed to psychic factors or to the needle puncture itself. It was par ticularly significant that the burning sen sation on injection, which sometimes oc curs with other anesthetics, was not present when Primacaine HC1 was used. This would appear to be attributable to the nonirritating qualities of this drug. There were no serious toxic reactions, and no allergic response was observed. In fact, several dentists who had developed a dermatitis of the hands from other anesthetics used Primacaine HC1 as a substitute and reported no recurrence of the dermatitis after several months had passed. Postinjection examination in the pres ent study disclosed no swelling or slough at the puncture site, and the few in stances of slight postinjection pain were attributed to needle trauma.
M O N H E IM . . . V O L U M E 50, J U N E 1955 ■ 635
Table •
S u m m a ry o f d a ta fro m
1 5 d e n t a l s c h o o ls r e g a r d i n g in j e c t i o n s o f P r im a c a in e H C I
Type o f o p e ra t io n
P r im a c a in e s o lu t i o n
° 1
4 ' °a Z
Ô -S u o
.
z
o
a Q) . .2 Q. 5 Ô e
cO o
,
0 2 5 T3 1— O Ü O
, a C =>
O_Q ÜHtÎo
2
c
"O 3 £ o
c o O a> o u O) > oE D o o JZ *o a c o o ' . c > .a o u < D ’o X *D o_ ‘o U J cn a_ Q o- £ Q U - ao_ "5 q
46
53
48
5
22
18
11
2
52
1
1 .5 % w ith p h e n y le p h r in e 1 :2 5 ,0 0 0
67
76
58
18
41
26
8
1
69
4
3
1 % w it h e p in e p h r in e 1 :5 0 ,0 0 0
151
166
135
31
8
78
8
152
11
3
5
1 . 2 5 % w it h e p i n e p h r in e 1 :5 0 ,0 0 0
34
35
18
17
11
16
8
27
5
3
1
1 ,1 0 0 1 ,2 0 8
782
426
581
516
82
29
1 ,1 0 7
70
30
11
53
3
3
3
3
12
11
2
1
4
13
1 . 2 5 % w it h e p in e p h r in e 1 :8 0 ,0 0 0
181
220
149
71
120
73
12
15
212
6
2
1 % w ith e p in e p h r in e 1 :1 0 0 ,0 0 0
142
164
43
121
81
64
18
1
143
15
6
1
1 . 2 5 % w it h e p in e p h r in e 1 :1 0 0 ,0 0 0
335
372
199
173
186
131
53
2
338
25
9
10
362
426
329
97
241
149
23
13
416
6
4
5
3
1 . 5 % w it h e p in e p h r in e 1 :1 5 0 ,0 0 0
110
111
66
45
51
52
8
102
7
2
2
1
1 .5 % w ith e p in e p h r in e 1 :2 0 0 ,0 0 0
159
169
111
58
51
84
26
165
3
1
2
1
1
1 . 5 % w it h e p in e p h r in e 1 :4 0 0 ,0 0 0
13
16
16
9
7
37
10
25
3
11
3
3
4
3
2
10
7
5
1
7
1 . 5 % w it h
ep in ep h rin e
P o s tin je c t io n
O
1 .5 % w ith n o e p in e p h r in e
1 . 5 % w it h e p in e p h r in e 1 :5 0 ,0 0 0
rh a g e
C
•ra 3
kj
H e m o r
T o x ic ity
A n e s t h e s ia
01 >
t/>
C
Type of in je c tio n
7
4
2
1
1
75
8
1 :1 0 0 ,0 0 0
T o ta l
2 ,7 0 0 3 ,0 1 6 1 ,9 5 4 1 ,0 6 2 1 ,4 7 4 1 ,2 1 4 2 5 7
8
12
71
2 ,8 0 4 1 5 3
7
4
67
6
35
36
434 • T H E JO U R N A L O F T H E A M E R IC A N D E N T A L A S S O C IA T IO N
In order that our findings may be compared with those of other groups that have investigated Primacaine HG1, a table is included summarizing data regarding some 3,000 injections made by staff members of 15 dental schools in the United States and Canada. It will be seen that the observations made else where correspond closely to ours with respect to the degree of anesthesia, ab sence of toxicity and to the postinjection picture. S U M M A R Y AND C O N C LU S IO N S
Primacaine HC1 is a potent local anes thetic with a low order of toxicity. It appears to diffuse more rapidly than
other commercially available local anes thetic solutions. No allergic manifestations were noted after administration of Primacaine HC1, although a number of patients who re ceived injections had had a history of allergic response to other preparations. The potency of the new local anesthet ic makes it possible to use lower con centrations of the anesthetic drug than are commonly employed and permits smaller epinephrine dilutions without sacrificing anesthetic depth. Results with this new anesthetic agent have been sufficiently satisfying to war rant further investigation; work is now in progress to determine further its ad vantages by comparative studies.
Dental materials and skills in oral and facial prosthesis
A. C. Fonder, D.D.S., Winnetka, III.
Rehabilitation of people with cleft palates, missing ears, noses, parts of the face and so forth by means of technics familiar to the dentist and dental mate rials found in every office can be so simple that no dentist can conscientiously ignore his responsibility for this service to the handicapped in his locality. These handi capped persons range from the recluses who have completely shut themselves off from society to those who have achieved some social adjustment. Both need physi cal rehabilitation. There are at present one quarter mil lion persons with congenital cleft palates,
and in all, well over a million handi capped people for whom surgery is con traindicated or impossible. They must turn to the somatoprosthetist for help, and he in good conscience must do his part. Special training and special talent is required to care for these handicapped people, but the average dentist has the talent and training to qualify him for this somatoprosthetic rehabilitation. The ideal solution of this problem is team work between surgeon, somatoprosthetist (dentist or physician), speech therapeutist and psychologist. Until there are suffi
Leonard. M . Monheim, D.D.S., Pittsburgh
A. new local anesthetic agent has been used for approximately a year in the clinic of the University of Pittsburgh School of Dentistry in order to determine its effectiveness for dental operative and surgical procedures when administered by block and infiltration technics. Chemically known as 2' diethylaminoethyl-2-butoxy-3-aminobenzoate hydro chloride, and issued under the brand name Primacaine HC1, the anesthetic is represented by this structural formula:
It was synthesized by Epstein and Myer.1,2 Chemical and physical proper ties and pharmacological data were de termined by the research department of Novocol Chemical Manufacturing Co., Inc. The new drug differs from local anes thetics of the butethamine and procaine types in that the amino group on the benzene ring is in the meta instead of the para position and a butoxy group is added to the ring’s 2 position. Primacaine HC1 occurs as a white crys tal with a melting point of 115° to 118° 633
C. It has a distilled water solubility of 75 per cent at room temperature and is stable to heat sterilization. Pharmacologically, Primacaine HC1 was found to have greater analgesic po tency than procaine, butethamine and metabutethamine, while subcutaneous and intraperitoneal toxicity studies place it in the procaine range. Because of its high analgesic potency, it may be used in a 1.5 per cent dilution while other anesthetic drugs are com monly furnished in 2 per cent and 4 per cent concentrations. The fact that clini cal testing with epinephrine dilutions of 1:200,000 and 1:400,000 indicated that these dilutions were sufficient to main tain anesthesia levels for periods of one to two hours suggests that the new anes thetic does not have vasodilator tenden cies. To determine whether excessive doses would produce systemic damage or local tissue irritation, two groups of rats re ceived daily injections of ten and 25
T h e m a t e r i a l u s e d in th is s tu d y w a s f u r n is h e d th r o u g h th e c o u r t e s y o f t h e N o v o c o l C h e m ic a l M a n u f a c t u r in g C o . , In c ., N e w Y o r k . F r o m th e d e p a r t m e n t o f a n e s th e s ia , U n iv e r s ity o f P it t s b u r g h S c h o o l o f D e n t is tr y . 1. E p s te in , E .; M y e r , M . , a n d G in s b e r g , H . E x p e r i m e n ts o f t o x i c i t y a n d lo c a l a n e s th e t ic a c t i v i t y o f a lk y / a m in o e th y l e s te rs o f m e ta a m in o a lk o x y b e n z o a te s . A c c e p t e d f o r p u b l i c a t i o n b y A n e s th e s ia a n d A n a l g e s ia R e s e a rc h J o u r n a l. 2 . E p s te in , E., a n d M y e r , M . M o n a a n d d i a lk y l a m in o e t h y l e s te rs o f m e ta a m in o a lk o x y b e n z o ic a c id s . U n p u b lis h e d .
634 • THE JO U R N A L O F T H E A M E R IC A N D EN T A L A S S O C IA T IO N
times the calculated human dose, and these animals were sacrificed at the end of a two week period for histological ex amination of the spleen, liver, kidneys and the muscle tissue at the injection sites. No variation was observed within the organs, blood counts were in the normal range, and the sites of the re peated daily injections showed no evi dence of irritation. The clinical studies at the University of Pittsburgh Dental School covered 470 injections on dental patients by the in filtration, mandibular, infraorbital and tuberosity methods. The cases in which it was used for surgical and for operative procedures were about equally divided. The Primacaine HC1 1.5 per cent solu tion was used with epinephrine dilutions which varied from 1:50,000 to 1:400,000; also included in the study were 20 injections of the 1.5 per cent solution without vasoconstrictor. The absence of a controlled study precluded a statistical evaluation at this time, but plans have been made to present a statistical com parison in a subsequent paper. DISCU SSIO N
All but one injection produced profound anesthesia, and the single instance which was classified as “fair anesthesia” followed the administration of the epinephrinefree solution. The group consisted of routine dental patients, taken as they presented themselves. None were selec tively excluded, but a number of indi viduals who had proved refractory to other anesthetic agents were included. Not a single anesthetic failure was en countered in the group of patients who had been refractory to other anesthetic drugs at previous appointments. The onset of local anesthesia was ex tremely rapid. In many instances it was estimated that surgical anesthesia was present within 30 to 45 seconds, while some patients volunteered the informa tion that they had experienced numb
ness before the needle had been with drawn. In practically every instance an esthesia was complete within a two minute period. Anesthesia duration was influenced by the vasoconstrictor concentration. In those instances in which the epinephrinefree solution was employed, duration ap proximated 30 minutes. The 1.5 per cent solution with epinephrine 1:50,000 gave a block anesthesia duration average some what in excess of three hours, while in filtration injections would last for 1f i to 2 hours. Epinephrine dilutions of 1:100,000, 1:125,000 and 1:150,000 produced anesthesia averages of about two hours. The epinephrine contents of 1:200,000 to 1:400,000 yielded proportionally briefer durations, but freer bleeding in the instances in which surgery was per formed was observed when the 1:400,000 solution was used. Because of the prolonged anesthesia and relatively minor incidence of toxicity, the optimum epi nephrine dilutions appear to be 1:50,000 and 1:125,000. Complications that arose during in jection or during the period of anesthesia were minor and few and, in most cases, could be attributed to psychic factors or to the needle puncture itself. It was par ticularly significant that the burning sen sation on injection, which sometimes oc curs with other anesthetics, was not present when Primacaine HC1 was used. This would appear to be attributable to the nonirritating qualities of this drug. There were no serious toxic reactions, and no allergic response was observed. In fact, several dentists who had developed a dermatitis of the hands from other anesthetics used Primacaine HC1 as a substitute and reported no recurrence of the dermatitis after several months had passed. Postinjection examination in the pres ent study disclosed no swelling or slough at the puncture site, and the few in stances of slight postinjection pain were attributed to needle trauma.
M O N H E IM . . . V O L U M E 50, J U N E 1955 ■ 635
Table •
S u m m a ry o f d a ta fro m
1 5 d e n t a l s c h o o ls r e g a r d i n g in j e c t i o n s o f P r im a c a in e H C I
Type o f o p e ra t io n
P r im a c a in e s o lu t i o n
° 1
4 ' °a Z
Ô -S u o
.
z
o
a Q) . .2 Q. 5 Ô e
cO o
,
0 2 5 T3 1— O Ü O
, a C =>
O_Q ÜHtÎo
2
c
"O 3 £ o
c o O a> o u O) > oE D o o JZ *o a c o o ' . c > .a o u < D ’o X *D o_ ‘o U J cn a_ Q o- £ Q U - ao_ "5 q
46
53
48
5
22
18
11
2
52
1
1 .5 % w ith p h e n y le p h r in e 1 :2 5 ,0 0 0
67
76
58
18
41
26
8
1
69
4
3
1 % w it h e p in e p h r in e 1 :5 0 ,0 0 0
151
166
135
31
8
78
8
152
11
3
5
1 . 2 5 % w it h e p i n e p h r in e 1 :5 0 ,0 0 0
34
35
18
17
11
16
8
27
5
3
1
1 ,1 0 0 1 ,2 0 8
782
426
581
516
82
29
1 ,1 0 7
70
30
11
53
3
3
3
3
12
11
2
1
4
13
1 . 2 5 % w it h e p in e p h r in e 1 :8 0 ,0 0 0
181
220
149
71
120
73
12
15
212
6
2
1 % w ith e p in e p h r in e 1 :1 0 0 ,0 0 0
142
164
43
121
81
64
18
1
143
15
6
1
1 . 2 5 % w it h e p in e p h r in e 1 :1 0 0 ,0 0 0
335
372
199
173
186
131
53
2
338
25
9
10
362
426
329
97
241
149
23
13
416
6
4
5
3
1 . 5 % w it h e p in e p h r in e 1 :1 5 0 ,0 0 0
110
111
66
45
51
52
8
102
7
2
2
1
1 .5 % w ith e p in e p h r in e 1 :2 0 0 ,0 0 0
159
169
111
58
51
84
26
165
3
1
2
1
1
1 . 5 % w it h e p in e p h r in e 1 :4 0 0 ,0 0 0
13
16
16
9
7
37
10
25
3
11
3
3
4
3
2
10
7
5
1
7
1 . 5 % w it h
ep in ep h rin e
P o s tin je c t io n
O
1 .5 % w ith n o e p in e p h r in e
1 . 5 % w it h e p in e p h r in e 1 :5 0 ,0 0 0
rh a g e
C
•ra 3
kj
H e m o r
T o x ic ity
A n e s t h e s ia
01 >
t/>
C
Type of in je c tio n
7
4
2
1
1
75
8
1 :1 0 0 ,0 0 0
T o ta l
2 ,7 0 0 3 ,0 1 6 1 ,9 5 4 1 ,0 6 2 1 ,4 7 4 1 ,2 1 4 2 5 7
8
12
71
2 ,8 0 4 1 5 3
7
4
67
6
35
36
434 • T H E JO U R N A L O F T H E A M E R IC A N D E N T A L A S S O C IA T IO N
In order that our findings may be compared with those of other groups that have investigated Primacaine HG1, a table is included summarizing data regarding some 3,000 injections made by staff members of 15 dental schools in the United States and Canada. It will be seen that the observations made else where correspond closely to ours with respect to the degree of anesthesia, ab sence of toxicity and to the postinjection picture. S U M M A R Y AND C O N C LU S IO N S
Primacaine HC1 is a potent local anes thetic with a low order of toxicity. It appears to diffuse more rapidly than
other commercially available local anes thetic solutions. No allergic manifestations were noted after administration of Primacaine HC1, although a number of patients who re ceived injections had had a history of allergic response to other preparations. The potency of the new local anesthet ic makes it possible to use lower con centrations of the anesthetic drug than are commonly employed and permits smaller epinephrine dilutions without sacrificing anesthetic depth. Results with this new anesthetic agent have been sufficiently satisfying to war rant further investigation; work is now in progress to determine further its ad vantages by comparative studies.
Dental materials and skills in oral and facial prosthesis
A. C. Fonder, D.D.S., Winnetka, III.
Rehabilitation of people with cleft palates, missing ears, noses, parts of the face and so forth by means of technics familiar to the dentist and dental mate rials found in every office can be so simple that no dentist can conscientiously ignore his responsibility for this service to the handicapped in his locality. These handi capped persons range from the recluses who have completely shut themselves off from society to those who have achieved some social adjustment. Both need physi cal rehabilitation. There are at present one quarter mil lion persons with congenital cleft palates,
and in all, well over a million handi capped people for whom surgery is con traindicated or impossible. They must turn to the somatoprosthetist for help, and he in good conscience must do his part. Special training and special talent is required to care for these handicapped people, but the average dentist has the talent and training to qualify him for this somatoprosthetic rehabilitation. The ideal solution of this problem is team work between surgeon, somatoprosthetist (dentist or physician), speech therapeutist and psychologist. Until there are suffi