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The clinical effectiveness of certain local anesthetics in dental procedures
ANESTHESIOLOGY .
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THE CLINICAL EFFECTIVENESS OF CERTAIN LOCAL ANESTHETICS IN DENTAL PROCEDURES Sidney Epstein, D.D.S., * Sun Francisco, Calif., and Neal W. Chilton, D.D.S,,#* Trenton, N. J.
T
study reported in this article was designed to measure objectively the clinical effectiveness of local anesthetic solutions in dental procedures. It was also conceived to determine whether or not data or criteria could be secured that would clearly define potency of local anesthetics in terms of clinical needs. All variables that could in any way influence the judgment of the clinicians were reduced to a minimum. The dentists who participated in this study were dental officers stationed at Fort George G. Meade, Fort Leavenworth, Fort Riley, and Walter Reed Army Hospital in 1954 and 1955. Although the project had no official Army authority, it was done with the knowledge and concurrence of the post dental surgeons. None of the opinions or data are in any way to be construed as representing opinions of the Department of the Army. They are solely those of the authors, who are appreciative of the cooperation of all who participated and made this work possible. HE
METHODS
AND MATERIALS
Three local anesthetic compounds were employed-procaine hydrochloride, lidocaine (Xylocainet) hydrochloride, and a then relatively new compound, All three compounds were used as meprylcaine (Oracainet) hydrochloride. 2 per cent solutions, and in addition a 4 per cent solution of procaine hydrochloride was also included. In order to limit consideration only to the anesthetic drug, the vasoconstrictor was kept as a constant. Therefore, epinephrine in a concentration of 1:50,000 was the drug of choice. In order *Associate Professor of Clinical Pharmacology, College of Physicians and Surgeons, a School of Dentistry; Chief of the Department of Dentistry, Mount Zion Hospital. **Associate Professor of Periodontics, Temple University School of Dentistry ; Assistant Professor of Periodontology, Graduate School of Medicine, University of Pennsylvania. txylocaine hydrochloride is a product of Astra Pharmaceutical Products, Inc., Worcester, Massachusetts. SOracaine hydrochloride is made by Oradent Chemical Company, Inc., New York, New York. 93
EPSTElN
94 CLINICAL
PROCEDURE
FOR
“BLIND
A1;D
0. s.. 0. Al. ii 0. I’. j‘inoary. 1Yi’)
CHILTON
TESTING”
LOCAL
ANESTHETIC
SOLUTIONS
1. One dental assistant will be selected to assume the responsibility for all injected anesthetics. 2. This assistant will complete all the information on the anesthetic record card marked “A” before giving the loaded syringe to the dental officer. 3. The assistant will also fill in the identification record on the postoperative card that is to be given to the patient. the dental officer will complete the following information 4. Before starting the injection, on the card: a. Medical condition b. Emotional state c. Procedure area d. Injection 5. The dentist will record or have recorded by his assistant the time in minutes when the initial injection was started. 6. The injection of the contents of the cartridge will be made in a constant time of one m&n&c. This interval is to be determined by use of a watch or an approximate second count using the method “one and two and three” up to “and sixty.” 7. Only one cartridge of solution will be provided to anesthetize an area for any given procedure. Therefore, the dentist must always reserve some of the contents of the cartridge for For all infiltration procedures, only one-half (%) supplementary injections (give example). If the anesthesia is not complete, the rethe contents of the cartridge is to be injected. mainder is to be given and this fact recorded. In this instance, the record is not classified I (C” unless the standard known solution is also injected to supplement the original injection. 8. If adequate onset of anesthesia is not evidenced within five (5) minutes after the initial time of injection, the grade of anesthesia will be recorded “C.” A standard known anesthetic of the dentist’s choice will then be injected to secure anesthesia necessary to eomplete the dental procedure. This information is also to be recorded. 9. Before the patient is dismissed from the chair, the dental officer will complete all spaces marked ‘ ‘ D ” on the record card and sign his name. 10. The patient will be given the postoperative information card with instructions to fill in the requested information and return it personally or through the message center within forty-eight (48) hours. 11. During the period of this anesthetic project, every injection of all anesthetic solutions will be recorded. This is to apply to both coded and unknown solutions. 12. The following criteria are to be followed in recording bleeding and reactions: a. Description of bleeding (1) No Bleeding. Normal operative field; alveolus fills to gingival crest after extraction with no free-flowing blood. (2) slight bleeding. Small amount of oozing after extractions or gingivo-plastic procedures that did not cause any difficulty in procedure or control of bleeding. (3) Moderate. Amount of bleeding could be controlled with moderate sponging and pressure. Did not interfere with ease of surgical procedure. Bleeding required frequent sponging and use of the aspirator. If (4) Excessive. tooth or bone fragments had to be located and removed, the amount of bleeding was considered a handicap and difficult to control. b. Reactions: (1) None. (2) Irritation-pain during period of injection. (3) If reactions occur, record how long after the time of injection. 13. Marking Cards a. Assistant will fill in all areas marked (‘A.” b. Dentist will fill in all areas marked ‘ ( B ” and will sign his name only when all areas (‘A” and “B” are filled in. c. “CT’ areas will be completed from patient’s postoperative return card. 14. When the patient’s postoperative record card is returned, it is to be stapled to the anesthetic record card. NOTE: This study is not an experiment of any new or untried All cartridges contain anesthetic formulas that are pharmacologically Z’here are no placebos. general use in American dentistry today. Fig.
I.-Procedure
sheet
given each
participating
anesthetic acceptable
dentist.
compounds. and in wide
Volume Number
I2 1
CLINICAL
EFFECTIVENESS
OF LOCAL
ANESTHETICS
95
t,o secure uniformity of dispensing that would prevent the visual identification of the solutions, the following criteria were established: One manufacturer (Oradent Chemical Company, Inc.) was asked to prepare procaine hydrochloride 2 per cent with epinephrine 1:50,000, procaine hydrochloride 4 per cent with epinephrine 1:50,000 and meprylcaine (Oracaine) hydrochloride 2 per cent with epinephrine 1:50,000. The lidocaine (Xylocaine) hydrochloride 2 per cent with epinephrine 1:50,000 was purchased in multiple-dose vials and Thus, four different reloaded into the standard 1.8 C.C. dental cartridges. solutions were employed, all packaged in identical glass cartridges supplied The cartridges with the same type and color of rubber stoppers and plungers.* were numbered from 1 to 100 with paper tabs and were supplied in boxes of The code was unknown to all clinicians, but the boxes 100 to each clinician. listed the four solutions employed in the study. Two boxes of these cartridges were submitted to the Council on Dental Therapeutics of the American Dental Association for analysis and assay. The results of this analysis are given in Table I. TABLE
SOLUTION A
B C D *Solution ?Slight
I.
ASSAY
OF THE
SOLUTIONS
PER CENT OF INDICATED AMOUNT OF ANESTHETIC COMPOUND
IDENTITY
Procaine hydrochloride 4% with epinephrine 1: 50,000 Procaine hydrochloride with epinephrine 1:50,000 Meprylcaine hydrochloride with epinephrine 1:50,000 Lidocaine hydrochloride* with epinephrine 1:50,000 was repackaged discoloration.
EMPLOYED
froln
multi-dosage
PER CENT OF INDICATED AMOUNT OF EPINEPHRINE
PH
109
98
4.0
105
110
4.0
102
105
3.9
108
79t
5.2
vials.
Each participating dentist was given a procedure sheet (Fig. 1)) 100 record cards+ (Fig. 2), and postoperative information slips (Fig. 3) for each box of 100 cartridges. After the data were accumulated, they were sent to one location for analysis. During the statistical analysis, the solutions were known only by letter until final evaluation was completed, at which time the solutions were identified. RESULTS
The data were tabulated and analyzed from four viewpoints : clinical effectiveness in obviating pain, onset of anesthesia, duration of anesthesia, and untoward side reactions. In Table II the results for the four solutions are tabulated according to clinical effectiveness, using grades A, B, and C of effectiveness as described in whom
*All solutions the authors tProvided by
nsed in wish to Cook-Waite
this study were packaged express their thanks. Laboratories, Inc., New
by
Oradent
York,
New
Chemical York.
Company,
Inc.,
to
EPSTETN
96
ANT)
0. s.. 0. \I. & 0. I’. .Innu.,ry, I’iiC>
CHILTOK
E’ig. 1. Analysis of these data by the chi-square technique results in a x? value of 5.004 for 4 dcgrces of freedom.’ lieference to standard tables of x2 discloses that this value can be equalled or exceeded by chance factors alone between
20 and 30 per cent of the time and can be called statistically not significant. When the data are retabulated so that only two grades of clinical effectiveness are employed (by grouping all B and C responses together), the same conclusion results. ANESTHETIC
NO.------
CLINIC
RECORD
NO.------
(1)
What time did “numb ” feeling disappear completely __-----(clock time). (2) Soreness after numb feeling left: None ( ) Much ( ) Little ( ) (3) How much soreness did you have the next day where the injection was made: None ( ) Much ( ) Little ( ) (4) Swelling : None ( ) Much ( ) Little ( ) (5) Bleeding : (extractions only) None ( ) Much ( ) Little ( ) Fig.
3.-Postoperative
information
carcl
given
each
patient.
Onset of anesthesia was determined as the time interval between the start of the injection and the first manifestation of anesthetic symptoms in the patient. Duration of anesthesia was obtained from the postoperative response TABLE
II.
CLINICAL
OF THE
SOLUTIONS
NO.CASESACCORDINGTOGRADEOFANESTHESIA A B I I
SOLUTION
Procaine 2% Procaine 4% Meprylcaine 2% Lidocaine 2% Totals
EFFECTIVENESS
173 190 189 179 731
(82.4%) (83.7%) (87.1%) (88.6%)
20
(9.5%)
21 (9.3%) I7 (7.8%) 15 (7.4%) 73
USED
C
17 (5.1%) 16 (7.0%) 1; gg.;wj . 0 52
TOTALNO. CASES
210 227 217 202 856
plmr
u
I,”
CLINICAL
EFFECTIVENESS
OF LOCAL
97
ANESTHETICS
slips by determining the time between the start of the injection and the time all symptoms disappeared as recorded by the patient. The results appear in Table III. TABLE
III.
ONSET
/
AND DURATION
1 AVER-
Is=-
OF ANESTHESIA
1
1
DURATION 1 STAND-
i
ANESTmTIC
Procaine 2oJo Procaine 4% Meprylcaine 2% Lidocaine 2% Procaine 2% Procaine 4v0 Meprylcaine 2% Lidocaine 2%
Conduction Conduction Conduction Conduction Infiltration Infiltration Infiltration Infiltration
76 90 85 108 83 107 114 104
3.11 3.29 3.06 2.94 2.69 2.51 2.49 2.44
1.63 1.71 1.48 1.65 1.53 1.34 1.41 1.16
35 47 55 57 51 52 64 54
2.78 2.55 2.67 3.73 2.36 2.37 2.56 3.22
8.97 6.42 7.19 8.24 7.25 8.94 10.32 10.91
2.55 2.47 2.53 3.83 2.18 2.18 2.18 3.03
Analyzing these data by normal curve techniques, it appears that there is no statistically significant difference in time of onset of anesthesia among the different solutions with a particular route of administration.2 In general, it does appear that infiltration anesthesia seems to produce a more rapid onset than does inferior alveolar nerve block. It appears that lidocaine has a longer duration than the other solutions, particularly when employed for nerve block. DISCUSSION
All of the data relative t,o the grade of anesthesia in all operative and surgical cases were pooled. The only criterion of complete anesthesia is freedom from pain. Therefore, there should be no differentiation between the degree of pain experienced, whether the procedure involves oral surgery or operative dentistry. Pooling gave a greater amount of data in the total gross figures. Approximately the same number of injections were given with each solution. In analyzing the grade of anesthesia, there is actually only one factor that can be clearly determined by the dentist and the patient. This is the complete absence of painful sensation in a dental procedure (either exodontia or restorative dentistry) which was recorded as grade “A” anesthesia. If, after administration of the anesthetic solution, there was still painful stimulation that did not permit the beginning or continuation of the dental operation without discomfort or hardship, this was recorded as grade “(2.” The degree of grade “B” anesthesia is somewhat nebulous. Who actually decides “injection not repeated, but patient complained of some pain”? Is it the patient who suddenly becomes stoical or fears a repeated injection, or who is apprehensive and not certain whether he is able to distinguish between pain, pressure, and anxiety and therefore indicates to the doctor that he may proceed? Or, is it the dentist who presumes that his technique for producing consistent anesthesia is accurate and therefore, in his eagerness to complete the dental treatment, proceeds anyway and records profoundness of anesthesia as grade “B”?
anesthesia in over X2 All four solutions provided effective grade “A” per cent of all injections. In this series there was no significant difference between procaine 2 per cent. and procaine 4 per cent, which produced grade “A” anest,hesia in 82.7 per cent and 83.7 per cent of t,he cases, respectively. Meprylcaine ant1 lidocaine also showed no clinically significant difference. They gave effective grade “A” anesthesia in 87.1 per cent and 88.6 per cent of injections, respectively. There were fewer grade “C” anesthesias for these two latter solutions. When the grade “B” anesthetic scores (graded on the basis that they represented acceptable anesthesia) were pooled with grade “A” scores, the four solutions provided anesthesia in the following order: 2 per cent procaine, 91.5 per cent ; 4 per cent procaine, 92 per cent; 2 per cent meprylcaine, 94.9 per cent, and 2 per cent lidocaine, 96.0 per cent. This does not represent a great spread in effectiveness. Analysis of the data by statistical methods indicates that, there is no stat,istical significance among the four local anesthetic solutions with respect to effectiveness. Apparently, the more potent anesthetics for routine dental procedures may be used interchangeably as far as effectiveness is concerned. Other attributes may have to be considered. Significant differences might have been demonstrated among the four solutions if the number of injections could have been increased, say, tenfold. The volume of solution injected was of necessity constant, because of the requirement that only a single unknown cartridge be used to secure anesthesia. No consistent attempt was made to determine whether or not effective Clinianesthesia could have been producd with a smaller quantity of solution. cal experience generally confirms the observation that skillful technique makes it possible t,o secure optimum anesthesia without expelling all the conterns of the anesthetic cartridge into the nerve site. The figures of this study show that the average dentist. in a. single cast, may inject a little bit less than a single cart ridge. Clinical observation indicates, however, that anatomic areas may require different volumes of solution. Dentists generally inject less solution for an infiltration than for conduction anesthesia. More solution will be expended to block the mandibular nerve than in infiltration of maxillary teeth. Of greatest concern to the dentist is the speed with which the anesthetic reaches its maximum effcctivcness so that he can work readily in a pain-fret operative area. This is usually measured as the time of onset of anesthetic sensation. Actually, the period of adequate profoundness follows after a latent period that begins with the initial sensations of warmth, tingling, or numbness. In mandibular block the onset generally will be experienced within about three minutes from t,hc start of the injection when the standard procaine 2 per cent with I :50,000 cpinephrine is used. For operative proccdurcs, thcrc This period may be shortel is usually effective anesthesia in four minutes. with those solutions t,hat arc used in a higher gram molecular concentration than procaine 2 per cent.
Volume 12 Number 1
CLINICAL
EFFECTIVENESS
OF LOCAL
ANESTHETICS
99
In the data reported, the onset for conductive anesthesia with 2 per cent lidocaine was 2.94 minutes, while with procaine 2 per cent it was 3.11 minutes. Infiltration was faster for both solutions. The time of onset recorded for an anesthetic solution was that period when symptoms of anesthesia began. It was not the period when the procedure could be started without pain. Therefore, the grade of anesthesia was determined not at the time onset was recorded but at the time work started. The average time at which the dentists began their treatment was about eight minutes after the initial injection. This long wait on the part of the dentists before they began the procedure was largely a matter of habit. Actually, little is gained in increased anesthesia by waiting more than two minutes beyond the indication of onset time which marks the beginning of penetration of the nerve fibers. In this study the participants were instructed to give the injection over a period of one minute. Therefore, they could not report that the patient had anesthesia before the injection was completed. It is our opinion that in those reports of the patient having anesthesia before withdrawal of the needle, the explanation will rest solely on an indication of the techniques and time of injection. The dentist who inserts a needle into tissue and rapidly expels the solution will have to wait just as long for anesthesia as one who injects slowly To evaluate statements that and deliberately as advocated by Jorgenson.3 the anesthetic was effective by the time the needle was removed from the site of injection, one must know how long the needle was in the tissue for the injection. In determining the induction or onset time, the area to be injected is probably more important than the solution. This fact is supported by the studies of Fiasconaro and associates4 They indicated that there is a similarity in induction time. Induction is shorter for infiltration than for conduction, and anatomic differences in the areas in which the injection is made will affect onset time. Induction time may be an almost meaningless feature in the evaluation of local anesthetics. Such information may prove to be nothing but a manufacturer’s gimmick. It is our opinion that it is completely unimportant whether a solution gives an onset time of 2.66 minutes or of 2.83 minutes. No one is that efficiency minded-even in America. The factors related to duration are of greatest importance. These not only encompass the time that the anesthetic is effective in preventing painful experience; they are also closely related to the action potential of the solution on the nerve fibers as well as the rate of metabolism. It is as incorrect to relate onset time to effectiveness of anesthetic grade as it is to conclude that the duration time is also the period of effective anesthesia during which surgery or operative dentistry may be performed withont pain. Evaluation of duration requires consideration of the character, quality, and amount of the vasoconstrictor activity inherent within the anesthetic
100
EPSTE
IK
AND
CHILTOK
0. s.. 0. 11. & 0 I’. Janu.,ry.
19FY
drug, as well as the amount, and the kind of vasoconstrictor drug that is added to the formula. Duration of anesthesia may be difficult to delimit, for it is related to several direct factors that, may have a significant effect on any values that are established. These factors are concerned with conditions at, the site of the nerve : A. The gram molecular concentration of the anesthetic B. The quant,ity of the drug administered. (I) The site of injection. (2) The rate of injection. C. The activity of the vasoconstrictor drug. (1) Concentration of the vasoconstrictor. (2) Quality of the vasoconstrictor. D. Metabolic activity and elimination.
drug.
In this study the amount of epinephrine used as the vasoconstrictor was within the usual assay limits of so-called commercial 1:50,000 epinephrine solutions of local anesthetic agent.s. The 4 per cent procaine had the shortest duration since procaine is a vasodilator, averaging 2.55 hours for conduction and 2.37 hours for infiltration anesthesia. The 2 per cent lidocaine, which may have some vehement vasoconstrictive activity as well as a slower rate of metabolism, had a duration of 3.73 hours and 3.22 hours in comparative procedures. In operative procedures only the actual manipulations attendant to preparation of a cavity or placement of a restoration are painful. When the operation is completed, there are no more acute sensations that necessitate anesthesia. Therefore, anesthetic solutions that, are effective far beyond the time needed to prepare and restore a tooth serve no real purpose. In surgical procedures, where there is trauma and laceration of tissues, there may be a reason for using a more prolonged anesthetic or even solutions that become analgesic. Even in this instance, however, there are certain limitations. There are more desirable, less limited, and possibly less toxic drugs that can be more wisely and selectively used or administered to control and relieve subsequent pain and apprehension. Often the patient’s objection to receiving a local anesthetic is not just the reaction to being given the solution. He dislikes the annoying discomfort of prolonged postoperative numbness, as well as the postoperative pain at the site of injection frequently caused by traumatic technique. For example, all too often a child patient is given an anesthetic that lasts far beyond the time necessary to complete the dental procedure. As a result he “chews up” his still anesthetized tongue, lips, or buccal mucosa. Another factor that is generally not considered in evaluating solutions of long duration is the physiologic penalty that is exacted. The residual anesthetic compound within the site of surgical interference keeps the nerve fiber “knocked out” so that it does not function. Tt is this prolonged lack of function that may interfere with normal physiologic procedures of recovery and repair.
CLINICAL
Volume 12
Number I
EFFECTIVENESS
OF LOCAL
101
ANESTHETICS
There is the further consideration, which Bjorlin5 points out, that the effect of a local anesthetic on living tissue is not confined to the temporary blocking of nerve endings, but that the anesthetic will have damaging effects upon the tissue that will vary with the concentration of the anesthetic and with the amount and quality of the vasoconstrictor added. Bjorlin’s excellent study gives weight to this premise. The average duration of treatment time in surgery and operative cases was twenty-five minutes, well within the duration time of anesthetic symptoms, This figure is an average that includes simple cavity preparation and plastic restorations as well as more extensive multiple restorations. It also includes single uncomplicated extractions as well as removal of impactions and more complex exodontia. In no instance was it reported necessary to reinject because of disappearance of effective clinical anesthesia. TABLE
Total
cases (906)
Type
of work
Type
of injection
Grade
of
Average Onset
(0) (8) I B
anesthesia
volume
A B C
injected
(minutes)
IV.
OF ANESTHETIC
DATA MEPRYLCAINE 2% (ORACAINE)
LIDOCAINE2vo (XYL~CAINE)
2% PROCAINE 219
4% PROCAINE
83 (85.8%) 30 (14.2ve)
184 (87.6%) 26 (12.4%)
195 (88.6%) 25 (11.4%)
202 (90.2%) 22 ( 9.8%)
92 (45.3%) Ill (54.7%)
99 (46.7%) 113 (53.3%)
102 (47.8%) 111 (52.2%)
81 (37.8%) 133 (62.2%)
173 (82.4%) 20 ( 9.5%) 17 ( 8.1%)
190 (83.7%) ;; [ ;.;w&y . 0
189 (87.1%) 17 ( 7.8%) 11 ( 5.1%)
179 (88.6%) 1; ) y‘q . 0
1.74 cc. 2.76
Average duration (minutes)
SUMMARY
231
1.76 C.C. 2.78
227
1.74 cc. 2.47
229
1.65 C.C. 2.54
of work
25.0
24.5
24.2
25.5
Average thesia
duration of anes(minutes)
152.0
143.0
147.5
203.0
Average
start
(minutes)
7.95
7.78
7.9
8.02
While duration of anesthesia is a most important consideration, it is important to emphasize that duration, as measured in this and other clinical studies, is not a determination of effective clinical anesthesia. It is actually a record of the patient’s report of duration of symptoms of anesthesia which are not significant to the dentist. Duration of clinical anesthesia is extremely difficult to ascertain. It may be best determined by the methods of Harris6 While all the solutions provided effective anesthesia beyond clinical requirements, it is felt that solutions of long duration should be used selectively rather than routinely. Anesthetic solutions should be selected by the den\ist in accordance with the dental procedure that he has elected to perform. Dental restorative and exodontic procedures generally do not last more than ninety minutes. Within
EPSTETK
AND CHILTOS
Volume 12 Number I
CLINICAL
EFFECTIVENESS
OF LOCAL
ANESTHETICS
103
this period of time, extensive treatment can usually be accomplished. If, for any reason, it is necessary to extend the procedure beyond this interval, reinjection is indicated. Even in the instance of dental surgical procedures, however, there is no justification for administering an anesthetic solution that lasts far beyond the operative period on the premise that it controls or relieves pain. As indicated above, there may bc better, more effective, controlled methods to alleviate postoperative distress which do not involve such great physiologic penalties or hazards. It is difficult to analyze satisfactorily the data on so-called side effects. Nine hundred and six patients returned the postoperative record slips (Table V). Postoperative edema and soreness were reported following 2 per cent procaine in eight patients, 4 per cent procaine in nine patients, 2 per cent meprylcaine in eleven patients, and 2 per cent lidocaine in four patients. In the instances of irnmediatc reactions of tremor, nausea, palpitation, irritation, perspiration, and fainting, the total number reacting for each of the four solutions was thirteen, seven, five, and seven patients, respectively. WC are unable to draw any conclusions as to relative toxicity from any of these data. In reviewing the records of the individual participating dentists, we found that the total numbers of reported side effects were more closely related to the dentists than to the anesthetic solutions. Some men observed their patients more critically. There also may have been a difference in attitude as well as in the manner of presentation of the postoperative record slip to the patient. It is also probable that the method of securing this information was not the most satisfactory or effective. SUMMARY
AND
CONCLUSIONS
Three local anesthetic drugs with 150,000 epinephrine as the vasoconstrictor were stuclied for effectiveness in obviating pain, onset of anesthesia, cluration of anesthesia, and toxicity as evidenced by side effects. From the data secured and analyzed, there were no statistically significant cliff erences in the parameters considered. If clinically important differences in local anesthetics are to be determined, a far greater number of patients than herrin reported will have to be stuclied or accurate laboratory criteria for evaluation will have to be cstablished and correlated. REFERENCES
Analysis in Dental Research, Washington, 1953, Office of Technical N. W.: Services, U.S. Department of Commerce, chap. 6. Analysis in Dental Research, Washington, 1953, Office of Technical Chilton, N. W.: Services, U.S. Department of Commerce, chap. 5. J. South. California D. A. 23: 30, 1955. Jorgenson, N. B.: Local Anesthesia, Determination of Clinical Dental Fiasconaro, J. E., Sherman, H., and Grundfest, H.: Local Anesthesia by Electrical Stimulations and Digital Plethysmography, J. Am. Dent. A. 54: 33, 1957. on Living Tissue in White Rats, Odontol. Bjorlin, G.: The Influence of Local Anesthetics Rev. 5: Supp. 2, 1954. Comparison of Several Clinically Used Local Harris, S., in Worley, R. C.: An Objective Anesthetics, Northwestern University D. Bull. 54: 5, 1954.
1. Chilton, 2. 3. 4. 5. 6.
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THE CLINICAL EFFECTIVENESS OF CERTAIN LOCAL ANESTHETICS IN DENTAL PROCEDURES Sidney Epstein, D.D.S., * Sun Francisco, Calif., and Neal W. Chilton, D.D.S,,#* Trenton, N. J.
T
study reported in this article was designed to measure objectively the clinical effectiveness of local anesthetic solutions in dental procedures. It was also conceived to determine whether or not data or criteria could be secured that would clearly define potency of local anesthetics in terms of clinical needs. All variables that could in any way influence the judgment of the clinicians were reduced to a minimum. The dentists who participated in this study were dental officers stationed at Fort George G. Meade, Fort Leavenworth, Fort Riley, and Walter Reed Army Hospital in 1954 and 1955. Although the project had no official Army authority, it was done with the knowledge and concurrence of the post dental surgeons. None of the opinions or data are in any way to be construed as representing opinions of the Department of the Army. They are solely those of the authors, who are appreciative of the cooperation of all who participated and made this work possible. HE
METHODS
AND MATERIALS
Three local anesthetic compounds were employed-procaine hydrochloride, lidocaine (Xylocainet) hydrochloride, and a then relatively new compound, All three compounds were used as meprylcaine (Oracainet) hydrochloride. 2 per cent solutions, and in addition a 4 per cent solution of procaine hydrochloride was also included. In order to limit consideration only to the anesthetic drug, the vasoconstrictor was kept as a constant. Therefore, epinephrine in a concentration of 1:50,000 was the drug of choice. In order *Associate Professor of Clinical Pharmacology, College of Physicians and Surgeons, a School of Dentistry; Chief of the Department of Dentistry, Mount Zion Hospital. **Associate Professor of Periodontics, Temple University School of Dentistry ; Assistant Professor of Periodontology, Graduate School of Medicine, University of Pennsylvania. txylocaine hydrochloride is a product of Astra Pharmaceutical Products, Inc., Worcester, Massachusetts. SOracaine hydrochloride is made by Oradent Chemical Company, Inc., New York, New York. 93
EPSTElN
94 CLINICAL
PROCEDURE
FOR
“BLIND
A1;D
0. s.. 0. Al. ii 0. I’. j‘inoary. 1Yi’)
CHILTON
TESTING”
LOCAL
ANESTHETIC
SOLUTIONS
1. One dental assistant will be selected to assume the responsibility for all injected anesthetics. 2. This assistant will complete all the information on the anesthetic record card marked “A” before giving the loaded syringe to the dental officer. 3. The assistant will also fill in the identification record on the postoperative card that is to be given to the patient. the dental officer will complete the following information 4. Before starting the injection, on the card: a. Medical condition b. Emotional state c. Procedure area d. Injection 5. The dentist will record or have recorded by his assistant the time in minutes when the initial injection was started. 6. The injection of the contents of the cartridge will be made in a constant time of one m&n&c. This interval is to be determined by use of a watch or an approximate second count using the method “one and two and three” up to “and sixty.” 7. Only one cartridge of solution will be provided to anesthetize an area for any given procedure. Therefore, the dentist must always reserve some of the contents of the cartridge for For all infiltration procedures, only one-half (%) supplementary injections (give example). If the anesthesia is not complete, the rethe contents of the cartridge is to be injected. mainder is to be given and this fact recorded. In this instance, the record is not classified I (C” unless the standard known solution is also injected to supplement the original injection. 8. If adequate onset of anesthesia is not evidenced within five (5) minutes after the initial time of injection, the grade of anesthesia will be recorded “C.” A standard known anesthetic of the dentist’s choice will then be injected to secure anesthesia necessary to eomplete the dental procedure. This information is also to be recorded. 9. Before the patient is dismissed from the chair, the dental officer will complete all spaces marked ‘ ‘ D ” on the record card and sign his name. 10. The patient will be given the postoperative information card with instructions to fill in the requested information and return it personally or through the message center within forty-eight (48) hours. 11. During the period of this anesthetic project, every injection of all anesthetic solutions will be recorded. This is to apply to both coded and unknown solutions. 12. The following criteria are to be followed in recording bleeding and reactions: a. Description of bleeding (1) No Bleeding. Normal operative field; alveolus fills to gingival crest after extraction with no free-flowing blood. (2) slight bleeding. Small amount of oozing after extractions or gingivo-plastic procedures that did not cause any difficulty in procedure or control of bleeding. (3) Moderate. Amount of bleeding could be controlled with moderate sponging and pressure. Did not interfere with ease of surgical procedure. Bleeding required frequent sponging and use of the aspirator. If (4) Excessive. tooth or bone fragments had to be located and removed, the amount of bleeding was considered a handicap and difficult to control. b. Reactions: (1) None. (2) Irritation-pain during period of injection. (3) If reactions occur, record how long after the time of injection. 13. Marking Cards a. Assistant will fill in all areas marked (‘A.” b. Dentist will fill in all areas marked ‘ ( B ” and will sign his name only when all areas (‘A” and “B” are filled in. c. “CT’ areas will be completed from patient’s postoperative return card. 14. When the patient’s postoperative record card is returned, it is to be stapled to the anesthetic record card. NOTE: This study is not an experiment of any new or untried All cartridges contain anesthetic formulas that are pharmacologically Z’here are no placebos. general use in American dentistry today. Fig.
I.-Procedure
sheet
given each
participating
anesthetic acceptable
dentist.
compounds. and in wide
Volume Number
I2 1
CLINICAL
EFFECTIVENESS
OF LOCAL
ANESTHETICS
95
t,o secure uniformity of dispensing that would prevent the visual identification of the solutions, the following criteria were established: One manufacturer (Oradent Chemical Company, Inc.) was asked to prepare procaine hydrochloride 2 per cent with epinephrine 1:50,000, procaine hydrochloride 4 per cent with epinephrine 1:50,000 and meprylcaine (Oracaine) hydrochloride 2 per cent with epinephrine 1:50,000. The lidocaine (Xylocaine) hydrochloride 2 per cent with epinephrine 1:50,000 was purchased in multiple-dose vials and Thus, four different reloaded into the standard 1.8 C.C. dental cartridges. solutions were employed, all packaged in identical glass cartridges supplied The cartridges with the same type and color of rubber stoppers and plungers.* were numbered from 1 to 100 with paper tabs and were supplied in boxes of The code was unknown to all clinicians, but the boxes 100 to each clinician. listed the four solutions employed in the study. Two boxes of these cartridges were submitted to the Council on Dental Therapeutics of the American Dental Association for analysis and assay. The results of this analysis are given in Table I. TABLE
SOLUTION A
B C D *Solution ?Slight
I.
ASSAY
OF THE
SOLUTIONS
PER CENT OF INDICATED AMOUNT OF ANESTHETIC COMPOUND
IDENTITY
Procaine hydrochloride 4% with epinephrine 1: 50,000 Procaine hydrochloride with epinephrine 1:50,000 Meprylcaine hydrochloride with epinephrine 1:50,000 Lidocaine hydrochloride* with epinephrine 1:50,000 was repackaged discoloration.
EMPLOYED
froln
multi-dosage
PER CENT OF INDICATED AMOUNT OF EPINEPHRINE
PH
109
98
4.0
105
110
4.0
102
105
3.9
108
79t
5.2
vials.
Each participating dentist was given a procedure sheet (Fig. 1)) 100 record cards+ (Fig. 2), and postoperative information slips (Fig. 3) for each box of 100 cartridges. After the data were accumulated, they were sent to one location for analysis. During the statistical analysis, the solutions were known only by letter until final evaluation was completed, at which time the solutions were identified. RESULTS
The data were tabulated and analyzed from four viewpoints : clinical effectiveness in obviating pain, onset of anesthesia, duration of anesthesia, and untoward side reactions. In Table II the results for the four solutions are tabulated according to clinical effectiveness, using grades A, B, and C of effectiveness as described in whom
*All solutions the authors tProvided by
nsed in wish to Cook-Waite
this study were packaged express their thanks. Laboratories, Inc., New
by
Oradent
York,
New
Chemical York.
Company,
Inc.,
to
EPSTETN
96
ANT)
0. s.. 0. \I. & 0. I’. .Innu.,ry, I’iiC>
CHILTOK
E’ig. 1. Analysis of these data by the chi-square technique results in a x? value of 5.004 for 4 dcgrces of freedom.’ lieference to standard tables of x2 discloses that this value can be equalled or exceeded by chance factors alone between
20 and 30 per cent of the time and can be called statistically not significant. When the data are retabulated so that only two grades of clinical effectiveness are employed (by grouping all B and C responses together), the same conclusion results. ANESTHETIC
NO.------
CLINIC
RECORD
NO.------
(1)
What time did “numb ” feeling disappear completely __-----(clock time). (2) Soreness after numb feeling left: None ( ) Much ( ) Little ( ) (3) How much soreness did you have the next day where the injection was made: None ( ) Much ( ) Little ( ) (4) Swelling : None ( ) Much ( ) Little ( ) (5) Bleeding : (extractions only) None ( ) Much ( ) Little ( ) Fig.
3.-Postoperative
information
carcl
given
each
patient.
Onset of anesthesia was determined as the time interval between the start of the injection and the first manifestation of anesthetic symptoms in the patient. Duration of anesthesia was obtained from the postoperative response TABLE
II.
CLINICAL
OF THE
SOLUTIONS
NO.CASESACCORDINGTOGRADEOFANESTHESIA A B I I
SOLUTION
Procaine 2% Procaine 4% Meprylcaine 2% Lidocaine 2% Totals
EFFECTIVENESS
173 190 189 179 731
(82.4%) (83.7%) (87.1%) (88.6%)
20
(9.5%)
21 (9.3%) I7 (7.8%) 15 (7.4%) 73
USED
C
17 (5.1%) 16 (7.0%) 1; gg.;wj . 0 52
TOTALNO. CASES
210 227 217 202 856
plmr
u
I,”
CLINICAL
EFFECTIVENESS
OF LOCAL
97
ANESTHETICS
slips by determining the time between the start of the injection and the time all symptoms disappeared as recorded by the patient. The results appear in Table III. TABLE
III.
ONSET
/
AND DURATION
1 AVER-
Is=-
OF ANESTHESIA
1
1
DURATION 1 STAND-
i
ANESTmTIC
Procaine 2oJo Procaine 4% Meprylcaine 2% Lidocaine 2% Procaine 2% Procaine 4v0 Meprylcaine 2% Lidocaine 2%
Conduction Conduction Conduction Conduction Infiltration Infiltration Infiltration Infiltration
76 90 85 108 83 107 114 104
3.11 3.29 3.06 2.94 2.69 2.51 2.49 2.44
1.63 1.71 1.48 1.65 1.53 1.34 1.41 1.16
35 47 55 57 51 52 64 54
2.78 2.55 2.67 3.73 2.36 2.37 2.56 3.22
8.97 6.42 7.19 8.24 7.25 8.94 10.32 10.91
2.55 2.47 2.53 3.83 2.18 2.18 2.18 3.03
Analyzing these data by normal curve techniques, it appears that there is no statistically significant difference in time of onset of anesthesia among the different solutions with a particular route of administration.2 In general, it does appear that infiltration anesthesia seems to produce a more rapid onset than does inferior alveolar nerve block. It appears that lidocaine has a longer duration than the other solutions, particularly when employed for nerve block. DISCUSSION
All of the data relative t,o the grade of anesthesia in all operative and surgical cases were pooled. The only criterion of complete anesthesia is freedom from pain. Therefore, there should be no differentiation between the degree of pain experienced, whether the procedure involves oral surgery or operative dentistry. Pooling gave a greater amount of data in the total gross figures. Approximately the same number of injections were given with each solution. In analyzing the grade of anesthesia, there is actually only one factor that can be clearly determined by the dentist and the patient. This is the complete absence of painful sensation in a dental procedure (either exodontia or restorative dentistry) which was recorded as grade “A” anesthesia. If, after administration of the anesthetic solution, there was still painful stimulation that did not permit the beginning or continuation of the dental operation without discomfort or hardship, this was recorded as grade “(2.” The degree of grade “B” anesthesia is somewhat nebulous. Who actually decides “injection not repeated, but patient complained of some pain”? Is it the patient who suddenly becomes stoical or fears a repeated injection, or who is apprehensive and not certain whether he is able to distinguish between pain, pressure, and anxiety and therefore indicates to the doctor that he may proceed? Or, is it the dentist who presumes that his technique for producing consistent anesthesia is accurate and therefore, in his eagerness to complete the dental treatment, proceeds anyway and records profoundness of anesthesia as grade “B”?
anesthesia in over X2 All four solutions provided effective grade “A” per cent of all injections. In this series there was no significant difference between procaine 2 per cent. and procaine 4 per cent, which produced grade “A” anest,hesia in 82.7 per cent and 83.7 per cent of t,he cases, respectively. Meprylcaine ant1 lidocaine also showed no clinically significant difference. They gave effective grade “A” anesthesia in 87.1 per cent and 88.6 per cent of injections, respectively. There were fewer grade “C” anesthesias for these two latter solutions. When the grade “B” anesthetic scores (graded on the basis that they represented acceptable anesthesia) were pooled with grade “A” scores, the four solutions provided anesthesia in the following order: 2 per cent procaine, 91.5 per cent ; 4 per cent procaine, 92 per cent; 2 per cent meprylcaine, 94.9 per cent, and 2 per cent lidocaine, 96.0 per cent. This does not represent a great spread in effectiveness. Analysis of the data by statistical methods indicates that, there is no stat,istical significance among the four local anesthetic solutions with respect to effectiveness. Apparently, the more potent anesthetics for routine dental procedures may be used interchangeably as far as effectiveness is concerned. Other attributes may have to be considered. Significant differences might have been demonstrated among the four solutions if the number of injections could have been increased, say, tenfold. The volume of solution injected was of necessity constant, because of the requirement that only a single unknown cartridge be used to secure anesthesia. No consistent attempt was made to determine whether or not effective Clinianesthesia could have been producd with a smaller quantity of solution. cal experience generally confirms the observation that skillful technique makes it possible t,o secure optimum anesthesia without expelling all the conterns of the anesthetic cartridge into the nerve site. The figures of this study show that the average dentist. in a. single cast, may inject a little bit less than a single cart ridge. Clinical observation indicates, however, that anatomic areas may require different volumes of solution. Dentists generally inject less solution for an infiltration than for conduction anesthesia. More solution will be expended to block the mandibular nerve than in infiltration of maxillary teeth. Of greatest concern to the dentist is the speed with which the anesthetic reaches its maximum effcctivcness so that he can work readily in a pain-fret operative area. This is usually measured as the time of onset of anesthetic sensation. Actually, the period of adequate profoundness follows after a latent period that begins with the initial sensations of warmth, tingling, or numbness. In mandibular block the onset generally will be experienced within about three minutes from t,hc start of the injection when the standard procaine 2 per cent with I :50,000 cpinephrine is used. For operative proccdurcs, thcrc This period may be shortel is usually effective anesthesia in four minutes. with those solutions t,hat arc used in a higher gram molecular concentration than procaine 2 per cent.
Volume 12 Number 1
CLINICAL
EFFECTIVENESS
OF LOCAL
ANESTHETICS
99
In the data reported, the onset for conductive anesthesia with 2 per cent lidocaine was 2.94 minutes, while with procaine 2 per cent it was 3.11 minutes. Infiltration was faster for both solutions. The time of onset recorded for an anesthetic solution was that period when symptoms of anesthesia began. It was not the period when the procedure could be started without pain. Therefore, the grade of anesthesia was determined not at the time onset was recorded but at the time work started. The average time at which the dentists began their treatment was about eight minutes after the initial injection. This long wait on the part of the dentists before they began the procedure was largely a matter of habit. Actually, little is gained in increased anesthesia by waiting more than two minutes beyond the indication of onset time which marks the beginning of penetration of the nerve fibers. In this study the participants were instructed to give the injection over a period of one minute. Therefore, they could not report that the patient had anesthesia before the injection was completed. It is our opinion that in those reports of the patient having anesthesia before withdrawal of the needle, the explanation will rest solely on an indication of the techniques and time of injection. The dentist who inserts a needle into tissue and rapidly expels the solution will have to wait just as long for anesthesia as one who injects slowly To evaluate statements that and deliberately as advocated by Jorgenson.3 the anesthetic was effective by the time the needle was removed from the site of injection, one must know how long the needle was in the tissue for the injection. In determining the induction or onset time, the area to be injected is probably more important than the solution. This fact is supported by the studies of Fiasconaro and associates4 They indicated that there is a similarity in induction time. Induction is shorter for infiltration than for conduction, and anatomic differences in the areas in which the injection is made will affect onset time. Induction time may be an almost meaningless feature in the evaluation of local anesthetics. Such information may prove to be nothing but a manufacturer’s gimmick. It is our opinion that it is completely unimportant whether a solution gives an onset time of 2.66 minutes or of 2.83 minutes. No one is that efficiency minded-even in America. The factors related to duration are of greatest importance. These not only encompass the time that the anesthetic is effective in preventing painful experience; they are also closely related to the action potential of the solution on the nerve fibers as well as the rate of metabolism. It is as incorrect to relate onset time to effectiveness of anesthetic grade as it is to conclude that the duration time is also the period of effective anesthesia during which surgery or operative dentistry may be performed withont pain. Evaluation of duration requires consideration of the character, quality, and amount of the vasoconstrictor activity inherent within the anesthetic
100
EPSTE
IK
AND
CHILTOK
0. s.. 0. 11. & 0 I’. Janu.,ry.
19FY
drug, as well as the amount, and the kind of vasoconstrictor drug that is added to the formula. Duration of anesthesia may be difficult to delimit, for it is related to several direct factors that, may have a significant effect on any values that are established. These factors are concerned with conditions at, the site of the nerve : A. The gram molecular concentration of the anesthetic B. The quant,ity of the drug administered. (I) The site of injection. (2) The rate of injection. C. The activity of the vasoconstrictor drug. (1) Concentration of the vasoconstrictor. (2) Quality of the vasoconstrictor. D. Metabolic activity and elimination.
drug.
In this study the amount of epinephrine used as the vasoconstrictor was within the usual assay limits of so-called commercial 1:50,000 epinephrine solutions of local anesthetic agent.s. The 4 per cent procaine had the shortest duration since procaine is a vasodilator, averaging 2.55 hours for conduction and 2.37 hours for infiltration anesthesia. The 2 per cent lidocaine, which may have some vehement vasoconstrictive activity as well as a slower rate of metabolism, had a duration of 3.73 hours and 3.22 hours in comparative procedures. In operative procedures only the actual manipulations attendant to preparation of a cavity or placement of a restoration are painful. When the operation is completed, there are no more acute sensations that necessitate anesthesia. Therefore, anesthetic solutions that, are effective far beyond the time needed to prepare and restore a tooth serve no real purpose. In surgical procedures, where there is trauma and laceration of tissues, there may be a reason for using a more prolonged anesthetic or even solutions that become analgesic. Even in this instance, however, there are certain limitations. There are more desirable, less limited, and possibly less toxic drugs that can be more wisely and selectively used or administered to control and relieve subsequent pain and apprehension. Often the patient’s objection to receiving a local anesthetic is not just the reaction to being given the solution. He dislikes the annoying discomfort of prolonged postoperative numbness, as well as the postoperative pain at the site of injection frequently caused by traumatic technique. For example, all too often a child patient is given an anesthetic that lasts far beyond the time necessary to complete the dental procedure. As a result he “chews up” his still anesthetized tongue, lips, or buccal mucosa. Another factor that is generally not considered in evaluating solutions of long duration is the physiologic penalty that is exacted. The residual anesthetic compound within the site of surgical interference keeps the nerve fiber “knocked out” so that it does not function. Tt is this prolonged lack of function that may interfere with normal physiologic procedures of recovery and repair.
CLINICAL
Volume 12
Number I
EFFECTIVENESS
OF LOCAL
101
ANESTHETICS
There is the further consideration, which Bjorlin5 points out, that the effect of a local anesthetic on living tissue is not confined to the temporary blocking of nerve endings, but that the anesthetic will have damaging effects upon the tissue that will vary with the concentration of the anesthetic and with the amount and quality of the vasoconstrictor added. Bjorlin’s excellent study gives weight to this premise. The average duration of treatment time in surgery and operative cases was twenty-five minutes, well within the duration time of anesthetic symptoms, This figure is an average that includes simple cavity preparation and plastic restorations as well as more extensive multiple restorations. It also includes single uncomplicated extractions as well as removal of impactions and more complex exodontia. In no instance was it reported necessary to reinject because of disappearance of effective clinical anesthesia. TABLE
Total
cases (906)
Type
of work
Type
of injection
Grade
of
Average Onset
(0) (8) I B
anesthesia
volume
A B C
injected
(minutes)
IV.
OF ANESTHETIC
DATA MEPRYLCAINE 2% (ORACAINE)
LIDOCAINE2vo (XYL~CAINE)
2% PROCAINE 219
4% PROCAINE
83 (85.8%) 30 (14.2ve)
184 (87.6%) 26 (12.4%)
195 (88.6%) 25 (11.4%)
202 (90.2%) 22 ( 9.8%)
92 (45.3%) Ill (54.7%)
99 (46.7%) 113 (53.3%)
102 (47.8%) 111 (52.2%)
81 (37.8%) 133 (62.2%)
173 (82.4%) 20 ( 9.5%) 17 ( 8.1%)
190 (83.7%) ;; [ ;.;w&y . 0
189 (87.1%) 17 ( 7.8%) 11 ( 5.1%)
179 (88.6%) 1; ) y‘q . 0
1.74 cc. 2.76
Average duration (minutes)
SUMMARY
231
1.76 C.C. 2.78
227
1.74 cc. 2.47
229
1.65 C.C. 2.54
of work
25.0
24.5
24.2
25.5
Average thesia
duration of anes(minutes)
152.0
143.0
147.5
203.0
Average
start
(minutes)
7.95
7.78
7.9
8.02
While duration of anesthesia is a most important consideration, it is important to emphasize that duration, as measured in this and other clinical studies, is not a determination of effective clinical anesthesia. It is actually a record of the patient’s report of duration of symptoms of anesthesia which are not significant to the dentist. Duration of clinical anesthesia is extremely difficult to ascertain. It may be best determined by the methods of Harris6 While all the solutions provided effective anesthesia beyond clinical requirements, it is felt that solutions of long duration should be used selectively rather than routinely. Anesthetic solutions should be selected by the den\ist in accordance with the dental procedure that he has elected to perform. Dental restorative and exodontic procedures generally do not last more than ninety minutes. Within
EPSTETK
AND CHILTOS
Volume 12 Number I
CLINICAL
EFFECTIVENESS
OF LOCAL
ANESTHETICS
103
this period of time, extensive treatment can usually be accomplished. If, for any reason, it is necessary to extend the procedure beyond this interval, reinjection is indicated. Even in the instance of dental surgical procedures, however, there is no justification for administering an anesthetic solution that lasts far beyond the operative period on the premise that it controls or relieves pain. As indicated above, there may bc better, more effective, controlled methods to alleviate postoperative distress which do not involve such great physiologic penalties or hazards. It is difficult to analyze satisfactorily the data on so-called side effects. Nine hundred and six patients returned the postoperative record slips (Table V). Postoperative edema and soreness were reported following 2 per cent procaine in eight patients, 4 per cent procaine in nine patients, 2 per cent meprylcaine in eleven patients, and 2 per cent lidocaine in four patients. In the instances of irnmediatc reactions of tremor, nausea, palpitation, irritation, perspiration, and fainting, the total number reacting for each of the four solutions was thirteen, seven, five, and seven patients, respectively. WC are unable to draw any conclusions as to relative toxicity from any of these data. In reviewing the records of the individual participating dentists, we found that the total numbers of reported side effects were more closely related to the dentists than to the anesthetic solutions. Some men observed their patients more critically. There also may have been a difference in attitude as well as in the manner of presentation of the postoperative record slip to the patient. It is also probable that the method of securing this information was not the most satisfactory or effective. SUMMARY
AND
CONCLUSIONS
Three local anesthetic drugs with 150,000 epinephrine as the vasoconstrictor were stuclied for effectiveness in obviating pain, onset of anesthesia, cluration of anesthesia, and toxicity as evidenced by side effects. From the data secured and analyzed, there were no statistically significant cliff erences in the parameters considered. If clinically important differences in local anesthetics are to be determined, a far greater number of patients than herrin reported will have to be stuclied or accurate laboratory criteria for evaluation will have to be cstablished and correlated. REFERENCES
Analysis in Dental Research, Washington, 1953, Office of Technical N. W.: Services, U.S. Department of Commerce, chap. 6. Analysis in Dental Research, Washington, 1953, Office of Technical Chilton, N. W.: Services, U.S. Department of Commerce, chap. 5. J. South. California D. A. 23: 30, 1955. Jorgenson, N. B.: Local Anesthesia, Determination of Clinical Dental Fiasconaro, J. E., Sherman, H., and Grundfest, H.: Local Anesthesia by Electrical Stimulations and Digital Plethysmography, J. Am. Dent. A. 54: 33, 1957. on Living Tissue in White Rats, Odontol. Bjorlin, G.: The Influence of Local Anesthetics Rev. 5: Supp. 2, 1954. Comparison of Several Clinically Used Local Harris, S., in Worley, R. C.: An Objective Anesthetics, Northwestern University D. Bull. 54: 5, 1954.
1. Chilton, 2. 3. 4. 5. 6.