Laboratory evaluation of analgetic effectiveness in human subjects

EXPERIMENTAL

435-456

(1963)

Evaluation

of

NEUROLOGY

Laboratory

7,

in H. School

SHERMAN,

Human

J. E.

Analgetic

Effectiveness

Subjects

FIASCONARO,

AND

H.

GRUNDFEST~

of Dental and Oral Surgery and the Department of Neurology, College of Physicians and Surgeons, Columbia University, New York Received

December

27, 1962

A method based on electrophysiological principles is described for evaluating actions of analgesic agents in controlled tests using electrical stimulation of the dental pulp. Some of the tests depended upon use of subjects who were selected according to an objective criterion of responsiveness to painful stimuli, characterized by digital plethysmography. Other subjects were selected on the basis of an observed correlation between the plethysmographic findings and the subjective reactions of different individuals to the electrical stimuli. About 25% of the individuals tested were rejected because of erratic plethysmographic records, erratic threshold to electrical stimulation in a preliminary test, or both. None of the individuals chosen by either criterion for subsequent testing reacted to administration of placebo. About two-thirds of the group responded with marked elevations of electrical threshold to orally administered acetylsalicylic acid (1.8 gm) or codeine (30 mg). The elevations caused by codeine were about three times as large as those induced by the acetylsalicylic acid. One-third of the subjects tested, or about 25% of the total population examined, proved refractory to 1.8 gm acetylsalicylic acid, and those subjects of this group who were also tested with 30 mg codeine also failed to respond to this analgesic drug. The present findings are in accord with clinical experience, but are discrepant with statistical evaluations using clinical material. Possible sources of error in the latter procedures are discussed. Introduction

Several recent reviews (1, 13, 16, 23, 24) have emphasized the deficiencies in the theoretical knowledge about pain and in the methods for its measurement and clinical evaluation. These deficiencies reflect upon the closely related problem of judging the effectiveness of analgesics. 1 Supported in part by a grant from Analgesic Research Fund, Department Surgeons, Columbia University.

the Bristol Myers Co. to the Anesthetic of Neurology, College of Physicians

435

and and

436

SHERMAN,

FIASCONARO,

AND

GRUNDFEST

Some investigators consider that laboratory studies on pain and on its alleviation are inaccurate to the point of being hopelessly useless, both as far as offering theoretical insight and as a practical tool for clinical applications. The data and the literature summarized in the above-mentioned reviews are, indeed, contradictory. Nevertheless, it seemed that a primary factor in the difficulties might be accounted for in terms of modern physiological data and that practical steps might then be taken to overcome the problems in the light of this analysis. The object of the present study therefore was to devise a theoretically and practically satisfactory method for eliciting and measuring pain in man. The most readily applied and accurately quantified method for exciting peripheral nervous pathways is by electrical stimulation. However, the use of electrical stimuli meaningful for eliciting the pain sensation is circumscribed by certain restrictions which arise from electrophysiological considerations (8, 10). In the course of the present work it was found that satisfactory solutions could be given to this and to several other difficulties posed by the characteristics of sensory physiology. The immediate purpose, to permit evaluation of analgesic drugs, also served as a check upon the validity of the method since there are available drugs of various grades of clinically accepted analgetic effectiveness which could serve as testing material. The experimental data reported here include two series of subjects, from work done about 3 years apart, with some differences in technique which will be described. The results of the two series, nevertheless, are entirely concordant. Principles

and

Methods.

A.

Electrical

Stimulation

to

Elicit

Pain

PrincipEes. Electrophysiological considerations (8, 10, 11) have led to the view that afferent nerve fibers have specialized receptor elements peripheral to the conductile portions of the axons. The conductile membrane of all axons is electrically excitable. In most cases, however, the receptor elements of sensory neurons are not excited by electrical stimulation, but by responding preferentially to specific, adequate stimuli they tend to initiate message patterns which are characteristic for the different sensory modalities. Thus, in the absence of specific stimuli for eliciting pain, or of methods for identifying and separately stimulating the pain afferents, it is unlikely that stimuli available for laboratory use can excite pain afferents alone. In the skin, pain-receptive nerve fibers are intermingled in various proportions with receptors for other sensory modalities. The axons reporting on painful stimuli to the central nervous

EVALUATION

OF ANALGESICS

437

system encompass a broad spectrum of fiber diameters and they belong to two physiologically and morphologically distinctive categories of mammalian nerve fibers, the A and C groups (cf. 17). Almost any type of stimulus to the skin, which is available in the laboratory, accordingly tends to evoke a message which involves several sensory modalities. The sensation evoked in the human subject or experimental animal may be far from intelligible in terms of experience gained with sensory data initiated by “natural” causes. The lack of specificity is particularly true for responses to electrical stimuli. These stimuli excite the axons independently of what type of specific stimuli activate the receptive surfaces of the sensory neurons. Thus, fibers of the same electrical threshold, but afferent for different sensory modalities may be excited by a given electrical stimulus (9, 12). A striking and perhaps an extreme example of the resulting modification of a sensory message is the failure of electrical stimulation of the chorda tympani nerve to evoke recognizable gustatory sensations, although this nerve is a major afferent pathway from the taste buds (4, 20). These considerations would seem to rule out the possibility of obtaining consistent and quantitatively meaningful data from the application of painful stimuli to the skin or to most afferent nerves. In a number of exploratory studies with various technical modifications we have satisfied ourselves that stimulation of the skin was, indeed, unsuitable to our purposes. While there are no readily accessible peripheral structures which yield only LLpure” pain sensations, the cornea and the dental pulp appear to have a predominant component of pain afferents. Thus, while both the cornea and the dental pulp probably have temperature and mechanoreceptors, pain is the overwhelming sensation elicited from these structures. Technical factors led to the choice of the dental pulp rather than the cornea1 surface as the site for applying the elecrical stimuli. From the above considerations it was hoped that the message evoked when electrical stimuli were applied to the teeth would be predominantly one eliciting painful sensations and would be less readily confusing to a group of untrained subjects. Similar considerations had impelled Ivy and his colleagues to adopt stimulation of the dental pulp for eliciting pain (6). The general method employed in the present study incorporates some of the procedures of these workers as well as some of the modifications subsequently made by Harris and Blockus ( 14). Instrumentation. The equipment used in the present work was based

438

SHERMAN,

FIASCONARO,

AND

GRUNDFEST

on that employed in earlier studies on dental anesthetics (5, 21). It underwent a number of modifications in the course of the period of about 3 years during which the data reported here were obtained. Only the equipment which is now in use will be described. The electrical stimulator (Fig. 1) was carefully designed to prevent in-

FIG. 1. Simplified circuit diagram of the electrical stimulator. The auto-transformer with a motor-driven center arm is the basic component. The motor is electrically position, with no current being delivered to reversible. Initially it is in the “down” the output. This condition is indicated by the “ready” light. Closing the “start” switch operates a relay which energizes the motor to rotate in the “up” direction. This is indicated by the “on” light. A full rotation takes 1 min. The linearly increasing current from the auto-transformer flows through an isolation transformer, into the output, from which it is delivered to the subject. The current also energizes the pen of a moving chart recorder. The range of maximum current can be selected as shown and the meter sensitivity is changed correspondingly so that the peak current at any setting gives full scale deflection on the recorder (4 of 9 positions shown in diagram). The output can be applied to any of six subjects through a “subject selector” switch (3 positions shown in diagram). The stimulating current can be stopped by the subject and by the operator. The motor then reverses, bringing the auto-transformer output to the zero position. Auxiliary circuits for measuring resistance in the stimulating circuit and for calibrating the equipment are not shown.

advertent delivery of dangerous currents.2 The stimulus was a 60-cycle alternating current applied through a high seriesresistor, so that changes in the electrical resistance of the subject were minimized. The current 2 Designed by Mr. ciate in the Department

George Katz, of Neurology.

Senior

Electronics

Engineer

and

Research

Asso-

EVALUATION

OF ANALGESICS

439

was increased at a constant rate and was recorded on a moving paper chart (Fig. 2). When the subject felt pain he pressed a switch which cut off the stimulus. The maximum current delivered during the tests could be varied by changing the resistance in the circuit. The sensitivity of the recording meter was changed correspondingly. The scale for a given individual was

FIG. 2. Sample records from tests on two subjects. The chart moved downward and the first test was on subject A. The current at first rose very slowly, and then commenced to increase linearly deflecting the trace to the right. When the subject responded by pressing a control switch the current ended abruptly. The tests on the two subjects were recorded on different scales of the instrument. Subject A (16-yearold male) had an initial threshold of 145 pa. Subject B (24-year-old female) had a threshold of 114 pa. Subject A then received 1.8 gm ASA and subject B an equal amount of placebo. A’ and B’ show the records of tests made 45 min later. The threshold of subject B remained unchanged while that of A had risen to 200ua, an elevation of 38%.

usually chosen so that the threshold current during the initial control period registered as an approximately half-scale deflection of the recording meter, or somewhat less (Fig. 2). Thus, the same scale could be employed to follow elevations of threshold up to 100yO or more. Since the elevations caused by acetylsalicylic acid were considerably smaller (Figs. 7-9; Tables l-3), the accuracy of the relative readings for a given experiment was thereby enhanced. In practice, accordingly, the durations during which the stimulating current was increasing to attain the threshold value were relatively constant for all the subjects, although the rates of rise of the currents varied, depending upon the absolute current thresholds. The durations were on the order of. 1.5 to 30 set and variations in reaction times of different subjects, or of the same subject under different conditions were therefore negligible. The subject could not tell at which moment the current began to rise and this factor as well as the slow rise of the current to its threshold value minimized the possibility that

440

SHERMAN,

FIASCONARO,

AND

GRUNDFEST

the subject could “guess” at some arbitrary endpoint. The data reported in the tables and in Figs. 4 to 9 are in terms of the peak currents attained when the subject responded. The threshold values of the current were quite constant for a given subject and underwent consistent changes when analgesic agent was applied. In the first series of seventeen subjects reported here (Tables 1, 2, and 4; Figs. 3-9) the digital plethysmographic responses to painful stimuli was used in addition as an objective criterion for pain, employing for this purpose a strain gage electronic plethysmograph ( 7). Earlier work (5, 2 1) in which the method is described had shown that the plethysmographic record (Fig. 3A) is a reliable criterion for painful sensation. However, the proper application of the volumetric cups to the subjects is time consuming. As experience was gained with the “subjective” method, utilizing signals by the subjects, and as this method was improved to minimize various errors, the routine use of plethysmographic recording was abandoned. Principles

and

Methods.

B. Subjects

and

Procedure

Principles. Various psychological factors are known to affect reactions to painful stimuli (1, 23, 24). There is also considerable individual

FIG. 3. Examples of plethysmographic records. A: Response of a subject during stimulation of a tooth. Beginning of stimulus (initiated by investigator) and its ending (by the subject) are indicated by marker on lower trace. Upward deflection in upper trace represents vasoconstriction which is always associated with diminution of digital pulse. B: Spontaneous variation of an individual who was judged unsuitable for tests. Both subjects had received 1.8 gm of placebo. Their respective electrical thresholds for subjective painful responses to stimuli are shown in Fig. 4.

EVALUATION

441

OF ANALGESICS

variation with regard to these factors and the capacity to discriminate pain. A number of experimental precautions were therefore taken which included the selection of subjects as the preliminary step. Initially, the basis of this selection was an observed correlation between the plethysmographic recordings and the reliability of subjective threshold determinations among different individuals. These correlations are shown in Figs. 3 and 4.

% 60

o..... IO

P

0-

40 min.

FIG. 4. (left). Another criterion for seIection of subjects. The two subjects represented in the graph had both received 1.8 gm (6 tablets) of placebo; A also had a plethysmographic response shown in Fig. 3A; B, with a plethysmographic record shown in Fig. 3B. Percentage change in threshold on the ordinate; time in minutes on the abscissa, in this and all the subsequent figures. FIG. 5. (right). Stability of threshold after administering placebo. Four of eight tests in Table 1 are plotted, each performed on a different individual.

Subject A exhibited a relatively steady plethysmographic record (Fig. 3A) and invariably responded to a painful stimulus with digital vasoconstriction. When this subject was tested for electrical threshold by his own subjective reaction (Fig. 4A) he respondedto a nearly constant level of applied current during a period of about 1 hour. Subject B exhibited an erratic plethysmographic record, with large sudden changes in finger volume even when no external stimulus was applied (Fig. 3B). The sub-

442

SHERMAN,

FIASCONARO,

AND

GRUNDFEST

jective measurements of threshold currents (Fig. 4B) also showed wide variation. All the subjects of the first series who exhibited plethysmographic records like that of Fig. 3B were discarded in the preliminary screening. It may be noted that individuals with this type of response fall into the category of “placebo reactors” (Fig. 4B), which has plagued the analysis of the analgetic actions of drugs (cf. 1, 24). None of the subjects chosen on the basis of the plethysmographic criterion proved to be “‘placebo reactors” (Figs. 4-6, 8, and 9; Tables 1, 2, and 4). In the second series of data we relied on the correlation described above and the subjects were put through an initial screening like that of Fig. 4 only. Individuals behaving like subject B were discarded. In no case did any of the subjects who were retained prove to be a placebo reactor (Tables 3 and 5). Procedure. In the first series to be reported the subjects were exclusively male dental students, between the ages of 21 and 26. In subsequent tests, however, the proportion of dental students decreased, and the subjects included dental hygienists, professional and nonprofessional hospital personnel and outpatient volunteers. The group reported in Table 3 were almost entirely nontechnical hospital personnel and outpatients, of both sexes, ranging in age between about 16 and 30 years. Only those individuals were used who had a single, one-surface (class I) silver alloy-silver amalgam filling in one or several posterior teeth. The teeth used for the tests had no carious material and the fillings were not in contact with gingival tissue. The region of the tooth to be stimulated was kept dry with rubber dam or cotton rolls. Several types of stimulating electrodes were used in the course of this study. The electrode which was finally adopted and used through most of the work reported here was a sharpened stainless steel dental instrument, carefully insulated everywhere except at the tip. The ground return was through a metal cardiographic electrode making contact with the subject’s forearm through cardiographic saline jelly. The stimulating electrode was applied to the tooth by hand with relatively constant pressure. The smooth rise of the current during a stimulation (Fig. 2) indicates that variations in current due to changes in contact resistance during a test were negligible. When it seemed advisable to do so, a depression of about 0.5 mm was made in the filling with a rotary no. s round dental bur. This prevented the electrode from slipping. However, the amalgam is a relatively good conductor and the precise site of the contact with the electrode was unimportant, since

EVALUATION

OF ANALGESICS

443

the resistance built into the stimulator was very large compared with that of the amalgam. Thus, as already noted, the threshold current for a given individual, as determined during the control period which preceded each experiment, was nearly constant throughout the series of tests, which for some individuals extended for more than 6 months and were never more frequent than once a week. The absolute thresholds for different subjects ranged between 7 and 200 pa. One factor causing this degree of difference probably resided in the character of the filling, and particulary in the extent of the cement base which might underly the filling. Since the currents used were relatively small and alternating, polarization at the tissue was probably negligible, particularly as the area of the effective electrode at the tooth was the contact surface of the latter with the amalgam filling. The subject held a switch (Fig. 1) with which he could stop the stimulus when pain was perceived (Fig. 2). Knowledge that termination of the stimulus, if it were painful, was under their control was an important factor in reassuring the subjects, and in making them willing to submit to the tests without special motivations. Many of the subjects were studied repeatedly. Their control electrical thresholds and plethysmographic responses, when the latter were recorded, were consistent over a long period of time. The first session for each new subject was confined to an orientation period to acquaint him with the nature of the experiment and to obtain a “dry run,” sometimes with administration of a placebo. As described above, this test indicated the subject’s ability to attain constant endpoints and in the second series it also served as the sole basis to select the subjects used. The initial sensation experienced by most subjects was that of a slight mechanical stimulus, which could be readily distinguished from the sensation of pain after both had been experienced. They dry run served to acquaint the subjects with these different sensations and they were asked to react only to the painful stimulus. This was the only training to which the subjects were exposed. Subsequent runs on the selected subjects were made at intervals at least one week apart, at which time determinations were made with administration of either a placebo (Fig. 5) or a drug (Figs. 7-9) under a variety of conditions. Each experiment usually began with a testing period lasting up to 1 hour, to determine the threshold for the subject on that particular day. Thus, a baseline was established for each test. However, as already noted, the threshold current usually varied little from one test period to

SHERMAN,

444

FIASCONARO,

AND

GRUNDFEST

another. The data were expressed as percentage changes in threshold in relation to these baseline values. All medications were administered orally. After the electrode had been placed on the tooth by one investigator, another initiated the stimulation by pressing a noiseless switch. Since the stimulus always began with zero current and increased slowly (Fig. 2) the subject was unable to judge the time at which the stimulation was begun. As already noted, the rate of rise of the current was adjusted for each individual, so that threshold was attained initially only after 1.5 to 30 set and the effects of changes of reaction times, or of “guessing” on the part of the subject must have been negligible. Figure 6 illustrates the effects on the electrical threshold of a subject

%-I x

5 min Intervals pa L 0.5 1 .

20 x 0

x x

-20 b

0w FIG. 6.

iiliy

20

(left). Effect of frequency of testing on stability of threshold. Subject had received 1.8 gm of placebo. Note erratic shifts in threshold when stimulations were delivered at O.S- and L-min intervals and return to a stable level when stimulation frequency was again decreased to 1 in 5 min. FIG. 7. (right). Analgetic effect of acetylsalicylic acid. Two tests on one individual made at Z-week intervals (subject T.H., Table l’)L A subsequent test on the same individual gave a greater peak elevation. Maximum change after placebo was + 5% in one test and no change in a second test (Table 1).

when successivetesting stimulations were applied at different frequencies. The initial and final measurementson this subject were obtained at S-min intervals, Although the total elapsed time was more than 1 hour, the values obtained were identical, except for two points which deviated by -10%. Between the two sequencesof measurementsat S-min intervals the tests were applied at shorter intervals, 0.5 and 2 min apart. The

EVALUATION

OF ANALGESICS

445

thresholds determined with these intervals varied by *2O%. Apparently some error is introduced by the higher testing frequencies, and in all the experiments reported here the testing stimuli were applied no more frequently than once in 5 min. In practice this permitted simultaneous study of several subjects, the investigator testing each in order (Fig. 2), and then repeating the cycle throughout the experiment. About 300 subjects have been studied during the past 3 years. Many have been tested with a variety of analgetic drugs and all were also examined after administration of a placebo. This report, which is chiefly concerned with describing the principles and methodology, will confine itself to presenting some data obtained with two well-recognized analgesics, acetylsalicylic acid and codeine, while subsequent publications will deal with several other varieties of analgetic agents. Acetylsalicylic acid and the placebo were administered as identical unmarked 0.3-gm tablets, using the “double blind” procedure. Codeine phosphate was given as a 30-mg tablet. However, this difference in presentation of the analgesic was also minimized by the mode of presentation of the stimulus. Furthermore, since all the tests were carried out for about 2 hours following administration of the agent each experiment constituted a curve with many points (Figs. 7-9). It is unlikely that the progressive elevation of threshold and the maintenance of that elevation which were always observed could have been due to random variations, or to bias on the part of the subjects or investigators.

The effectiveness of analgetic actions of the drugs reported on here, or in other studies to be described elsewhere, bore no relation to the age, sex or color of the subjects. As already noted, none of the individuals selected for testing proved to be placebo reactors. Figures 4 to 9 give the complete data on eight experiments involving placebo, eight in which acetylsalicylic acid was given, and two with administration of codeine. Analgetic Eflects of Acetylsalicylic Acid. Tables 1 to 3 summarize the data on subjects in the two series in which acetylsalicylic acid was used who responded with elevations in electrical threshold. Doses of the analgesic lower than 1.8 gm (6 tablets) were tested in a preliminary series of experiments, but the data are not shown since the results were erratic. However, the 1.8-gm dose gave a marked elevation of the threshold current to elicit pain. The time course of the change and its magnitude tended to be similar in different experiments on the same subject (Figs. 7-9).

446

SHERMAN,

FIASCONARO,

AND

GRUNDFEST

Some variation was observed under different experimental conditions. Thus, if the subject had eaten a meal before the test (Fig. 8Bz), or had a cold (B3), the onset of the analgetic effect was slower and its degree was less than in the standard condition (B,). When different teeth of the same subject were used for the tests (Fig. 9B1 - B3) there was only a small

%r I

% 140

0 20 40 60 a0 100 0 20 40 60 80 100 FIG. 8. (left). Changes in effectiveness of analgetic action of acetylsalicylic acid under different experimental conditions. Subject H.I. (Table 2): B,, empty stomach; B,, a full breakfast; B,, empty stomach, severe cold. Another experiment under same conditions as in B, (not plotted) gave a peak elevation of 52%. C, larger elevation of threshold after 30 mg codeine. Another experiment (not shown) is included in Table 2. P, absence of change in threshold after administration of placebo (one of two identical sets of data). FIG. 9. (right). Tests of analgetic effects made on different teeth of one subject (M.A., Table 2). Graphs B, (acetylsalicylic acid) ; C (codeine) and P (placebo) are from data obtained on stimulating one tooth. Be, B, show subsequent tests of effects of acetylsalicylic acid, eachon a different tooth. Two other experiments with similar results are not shown in the figure (Table 2). Only the first and last points for curve P are shown. The subject had a peakchangeof -2% (Table 2).

degree of variation, The times of onset of the analgetic effects were similar in different subjects. However, the rate of elevation of the threshold and the degree of elevation varied. The duration of the analgetic effect of 1.8 gm acetysalicylic acid was longer than 2 to 3 hours, the period during which the effects were examined in the laboratory.

EVALUATION

447

OF ANALGESICS

The average elevation of threshold for the sixteen tests on seven subjects presented in Table 1 was 40%. Five other subjects of the same series on whom fourteen tests were made (Table 2) showed an average threshold elevation of 45%. Fifty-eight other tests which were made on forty subjects more than 2 years later (Table 3) with an entirely different stimulator and somewhat different techniques yielded an average elevation of 25%. It will be noted, too, that in more than fifty tests with placebo on these subjects only a few elevations were observed and none exceeded an average of 5%. TABLE COMPARATIVE SEVEN

EFFECTS SUBJECTS

OF PLACEBO SELECTED

ON THE BASIS

Subject

Placebo

T.R. T.H. R.O. H.E. B.R. B.A. Ml. Total Averaee

1

AND OF 1.8 GM

8

16

elevation

0

40

SUBJECTS

Subject of placebo0

Effect of ASA 1.8 gm

Effect of codeine 30 mg

SELECTED

OF PLWEBO, ON THE

43, 40, 36 80, 53 71, 75 20 30

change in peak stimulating current in Tables 1, 2 and 4 were male dental

TABLE EFFECTS

BASIS

0 0

following students,

2

ACETYLSALICYLIC

H.I.

IN

ASA (%I 40, 40, 24, 24, 25, 23 25

no. of tests

COMPARATIVE

(ASA)

RECORDS~

(%)

0 +-$0 0 0 0 0 0

0 Data expressed as percentage administration of agent. All subjects between the ages of 21 and 26 years.

Effect

Acm

ACETYLSALICYLIC

OF PLETHYSMOGRAPHIC

ACID AND CODEINE

OF PLETHYSMOGRAPHIC

M.A. -2

S.T.A.

IN FIVE

RECORD+

S.A.

Y.A.

0

0

0

75 26 58 52

60 52 54 58 54

20 20 0

45

50

140 140

167

100

200

100

a Percentage change in peak stimulating b Total number of tests with placebo, elevation 0, 45, and 1410/o, respectively.

current 6; with

after administration of agent. ASA, 14; with codeine, 6. Average

number

0 0 0 0 0 0 0 0 0 0 0 0, 0 0 0

16 24

17 26

16 25

26 24

25 22 23

25 22

22 23

58;

0, 10 0

16 16

average

8

0

22

ASA,

Placebo 0 0

with

TABLE

3

50

12 25

0,

35, 11,

ASAa

27 20

elevation,

13 30 30

20 40

20, 50,

40, 30, IO 15

60 30

15, 20

23, 45,

12, 15 25, 25

25,

15, 35,

17,

35, 34,

25%.

10

10 20

AS. T.Mc. H.R. J.P. B.P. B.T. B.M. M.Me. A.K. A.D. A.N. B.W. C.T.

A.G.

A.W. E.V. J .R.O. A.M. J.M. A.E.

Subject

OF THRESHOLD TO PLACEBO AND TO 1.8 GM ACETYLSALICYLIC FROM TABLE 5 SELECTED BY “SUBJECTIVE” METHOD

23 22

Age

ELEVATION

of tests

F M M F M F M F M F M M F M M M F M M M

M.G. M.S. M.W. B.J. JeG. Ja.G. A.A. E.A. A.B. S.B. A.D. Dr.F. M.M. S.P. M.Sch. A.T. C.M. J.R. B.F. D.T.

0 Total

Sex

Subject

PERCENTAGE

M

M

F F M F M M F F M M M M M M M M F F

Sex

Acl~

23

25 20 23

26 25

22 26

28

21 21 22

0 0

0 0

0 0 0

0 0

0

0 0 0

0 16

0

18

0 0

0

0 0

Placebo

SUBJECTS

24 20

16

17 21

25

Age

OF FORTY

24 20

25 30

20

10

20

30 12

8

25 30 30

30 30

40

10

15

40 53

ASAa

% m

EVALUATION

OF

449

ANALGESICS

Effects of Codeine. The five subjects who showed an average elevation of 45y0 with acetylsalicylic acid were also tested following administration of codeine (Table 2). The elevation produced by the codeine was in every case greater than that following administration of the acetylsalicylic acid. Six tests in all were performed on the five subjects and the average elevation was 141%. Comparisons of the time course of the elevation with codeine and acetylsalicylic acid are shown in Figs. 8 and 9. The analgetic effect began earlier after administration of codeine and was still near its peak level at the end of the testing period. Individuals Who Did Not React to Analgesics. Table 4 summarizes data on five subjects of the first series who did not react with elevation of threshold to either acetylsalicylic acid or to codeine. We could find TABLE CORRELATION SELECTED

BETWEEN

FAILURE

BY PLETKYSMOGRAPHIC

Subject Effect

of placeboa

4 TO ASA

TO RESPOND CRITERION

AND

TO CODEINE

; PERCENTAGE

BAR

OK1

STE 0

0

0

0

0

0

0

Effect of codeine 30 mg

0

24

0

number

of tests with

placebo,

5; with

ASA,

SUBJECTS

OF THRESHOLD

AZ

Effect of ASA 1.8 gm

D Total

IN FIVE

ELEVATION

STER 0

0 (3 tests)

0

0

7; with

0

codeine,

5.

nothing in their histories to which their insensitivity might be ascribed. Seven other individuals in this group of subjects also failed to respond to either placebo or 1.8 gm of acetylsalicylic acid, but were not tested with codeine. The data on two later groups of subjects, fifty and eighty-five in number, respectively, are summarized in Table 5. Approximately 25% TABLE DISTRIBUTION

Total

no.

OF Two

Not

POPULATIONS

“Erratic” tested further

85

18 (36%) 20 (24%)

135

38 (28%)

50

a All were classified by subjective ing in age between 16 and 30 years.

5

OF SUBTECTS

AMONG

DIFFERENT

Reacting to 1.8 gm ASA

CATEGORIES~

Unreactive to 1.8 gm ASA

25 (50%) 40 (47%)

7 (14%) 25 (29%)

65 (48%) testing

alone.

Subjects

32 (24%) were

of both

sexes, rang-

450

SHERMAN,

FIASCONARO,

AND

GRUNDFEST

of the total were rejected on the basis of erratic electrical thresholds. Presumably all or most of them would have been placebo reactors, since none/ of the individuals retained for further studies reacted to placebos. However, another 25% of the total number failed to respond to 1.8 gm acetylsalicylic acid, or to other analgesics with which they were tested (unpublished data). None of the latter agents were found to be as effective in their analgetic action as is codeine, but several were considerably more potent than the acetylsalicylic acid. It is clear from Table 4 that many and, perhaps, all of the “unreactive” group of Table 5 would have shown little or no response to codeine. The remainder, about 50% of the total population, responded with elevations of electrical threshold to 1.8 gm of acetylsalicylic acid and other agents. Detailed data on the forty subjects in the second group of Table 5 are shown in Table 3. Discussion

The data indicate that clear-cut elevation of threshold to painful electric stimuli could be obtained with administration of 1.8 gm of acetylsalicylic acid, with the technique used. Administration of 30 mg codeine caused a still higher elevation of threshold. We cannot account for the discrepancy between our data and the conclusion of Beecher and co-workers (2) that oral administration of 60 mg codeine had no greater effect in relieving clinical pain than did a placebo. Strand, Henniger and Dille (22), using a somewhat similar electrical testing method to that described here, reported that the effects of a small dose of acetylsalicylic acid (0.3 gm) could be detected. However, the change of threshold became significant according to their criteria only at 90 min after administration of this quantity of the drug. Our own tests with dosages of acetylsalicylic acid lower than 1.8 gm were not carried on as long as 90 minutes after administering the drug. Comparisons of the data (22) with the present experiments are only rough, however, because of the different modes of presentation, and because our subjects were selected as described. Thus, the magnitudes of the elevations differed markedly. In their work, 0.3 gm acetylsalicylic acid increased the threshold by 10% while 30 mg codeine elevated it by about 25%. In the present work the average elevations for the first series of subjects (Tables 1 and 2) were 43% with 1.8 gm acetylsalicylic acid and 141% with 30 mg codeine. It should be noted that in the present work the large elevation was observed on administering codeine without acetylsalicylic acid. The

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potent&ion of the combination and of other analgesics will be described in other studies. Harris and Blockus (14) obtained equal elevations of threshold following oral administration of 0.65 gm of acetylsalicylic acid or placebo in data which were averaged for ten subjects. This finding would seem to be in accord with our inability to detect clearly the analgetic effects of less than 1.8 gm of acetylsalicylic acid. Intramuscularly administered “placebos” of NaCl caused no elevation in the averaged thresholds for another group of nine subjects, while 64 mg codeine phosphate did lead to a small elevation, Not only the different routes of administration of the agents, but also the different modes of presenting the data prevent comparison of this earlier work with that reported here. Insofar as the data of Harris and Blockus (14) may be analyzed from the averaged values of their Tables 2 and 6, their subjects were a mixed population, belonging to all three groups which are classified in Table 5, above. This admixture would vitiate also the elaborate statistical analysis employed in the earlier work. The data of Hardy, Wolf and Goode11 (13) are not comparable with those of the present work. These investigators used thermal stimuli applied to the skin from a radiant source. Furthermore, the subjects studied had received a considerable degree of training in determining the endpoint. The present data are in distinct contradiction with the conclusion of Beecher (1) that laboratory evaluation of analgesics, using electrical or other methods for eliciting pain, are valueless. The data presented above, and a large amount of other data on a variety of analgesics (to be published) demonstrate clearly that reproducible quantitative results can be obtained under the conditions which we have described. Our findings also appear to throw some light on possible sources of error which may be involved in a statistical evaluation of clinical reports on analgesics, such as Beecher favors. One of the possible sources is the incidence of placebo reactors. In the course of our examination of a large group of individuals it became apparent that some 20% to 30% exhibited erratic thresholds to the initial test, either with or without administration of placebo. It is noteworthy that once this group was eliminated none of the remaining individuals tested reacted to placebos. It is also noteworthy that the incidence of placebo reactors in various clinical studies averaged about 35% ( 1, Table 3.1))

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or about the same as the incidence of “erratic” subjects who were eliminated from our tests. Beecher also notes (1, p. 68), citing a variety of data (2, 15, 19), that “the focus could be sharpened a good deal in appraisal, for example, of effectiveness of acetylsalicylic acid administered orally when the placebo reactors were excluded from consideration.” It would seem that a similar statement should also be true for the case of other analgesics, including morphine and codeine. Jellinek (15) had suggested that exclusion of placebo reactors was a proper statistical procedure in the case of clinical evaluation of analgetic actions. Beecher, however, believes that elimination of placebo reactors may be “tampering with data” and “questionable” ( 1, p. 68). In our first series of tests, exclusion of subjects was not on the basis of their erratic electrical thresholds, but on the basis of their plethysmographic records. The absence of placebo reactors among any of the subjects used in that series therefore cannot be regarded as “tampering” with the data on the electrical threshold. The identification of individuals exhibiting erratic plethysmographic and/or subjective thresholds with placebo reactors which has been made above, is an inference, based on the fact that once these individuals were eliminated no placebo reactors were observed among the subjects tested in the present work. In point of fact, the erratic threshold shown in Fig. 4B represented diminution as well as elevation about a mean level. However, Lasagna and co-workers (19) have also noted that repeated exposure to placebo could produce variable responses. In other words, placebo reactors may be regarded as individuals who exhibit more or less random variations in responsiveness. If, as we believe, the plethysmographic and electrical tests can discriminate between placebo reactors and those who do not so react, the procedures might be useful for other purposes. For example, Beecher (1) notes that the placebo reactor is a recognizable psychological type, but recognizable “only with the aid of an intensive interview, plus psychological testing” (1, p. 69). The tests which we employed to exclude placebo reactors can be carried out on a half-dozen subjects in about 2 hours.3 a Digital plethysmographic recordings made in correlation with psychological tests during World War II and subsequently (Grundfest, unpublished) also indicated that a particular psychological type could be distinguished by means of erratic records like that of Fig. 3B.

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A second source of error which may enter into clinical testing of analgesics arises because a proportion of the population appears to be refractory to analgesics. Our own data on this score are insufficient for statistical analysis. However, among the subjects studied for this work, approximately 25% were found who did not respond to acetylsalicylic acid (Table 5) and to agents of approximately equal analgetic effectiveness. None of these subjects were tested with very potent analgesics. Therefore it cannot be stated firmly that the absence of response to the analgesics was not an accident of the technique. However, of five refractory subjects tested in the first series with codeine, only one showed an elevation of threshold and only of 24% (Table 4). Furthermore, one subject of the latter group was tested three times with acetylsalicylic acid, exhibiting no elevation at any time. That some individuals are relatively refractory to dental anesthesia by injections of local anesthetics is well known, and a few cases have been studied with some of the present techniques ( 2 1) . Lasagna and Beecher (18) found that a large dose of morphine (15 mg per 70 kg body weight) relieved only 75% of cases with clinical pain. A large part, or perhaps all, of their negative findings may be ascribed to the inclusion of individuals who are relatively refractory to analgesics. Furthermore, the conclusion (1, p. 67) that morphine relieves pain in only about twice as many individuals as does placebo, which was effective in about 35% of the tests, is probably invalid because of the admixture of placebo reactors in the statistical evaluations. The implications of the conclusions cited, that both morphine and codeine may be relatively ineffective in relieving pain, are contrary to the present findings with respect to codeine and to clinical experience with respect to morphine as well as codeine. It deserves to be noted that the tests which have been described here could be carried out on a population with clinical pain. The combination of the approaches developed by Beecher and his colleagues and of the methods of laboratory evaluation might prove very rewarding. The errors which are introduced by the existence of a large proportion of placebo reactors on the one hand, and of refractory individuals on the other (Tables 4 and 5)) can also vitiate laboratory studies on analgesics, if reliance is placed on the statistical averaging of an unselected subject population. This may account for the conflicting data of Ivy and his colleagues (6)) and of the subsequent studies by other members of the same group (14) _ These data and discrepancies have been extensively discussed by Beecher ( 1) .

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The mechanisms by which the analgesics cause elevations of electrical threshold for painful reactions are not elucidated in the present work, but some deductions are permissible. The electrical stimuli very probably bypass the specific receptors of the sensory fibers. It is therefore unlikely that analgesics, such as acetylsalicylic acid, exert a pharmacological action on the peripheral receptive mechanisms, unless they act by lowering the excitability of the axons to the electrical stimuli. This possibility is unlikely and elevation of electrical threshold for perception of pain thus implies that the number of impulses arriving at the central nervous terminals of the afferent nerves must be increased, whether because the stronger stimuli cause nerve fibers to fire more frequently or excite more nerve fibers. Both effects are possible, but the second is probably the more important agency for overcoming the analgetic action. Thus, it seems likely that the major and perhaps the exclusive sites of action of analgesic drugs lie within the central nervous system. Reactions to placebos, of course, also operate at central levels. The known and surmised electrophysiological and pharmacological complexities of the central nervous system may provide some further clues to the discrepancies observed in evaluating analgesic drugs with clinical and laboratory methods. Although the existence of “fast” and Wow” pain is doubted by some authorities (cf. 23), it seems to be a rather general experience, nevertheless, that pain evoked from the viscera, or from vascular smooth muscle, or the pain which is elicited from the hand after tourniquet block had eliminated A fibers, differs qualitatively from the bright sharp pain which is presumably carried in fibers of the A group (cf. 17). Afferent messages from different parts of the body must involve different neuronal circuits. The differences are further compounded when the afferent pathways include A and C fibers. Should the different neuronal components also vary in their pharmacological characteristics one might expect that “natural” pain from different sites might respond differently to various pharmacological agents. The same considerations also place restrictions on the interpretation of laboratory evaluations of analgesics, and of their carry-over into application. Electrical stimulation of dental pulp excites only one of the possible pathways for reporting pain. The pharmacological agents found to be efficacious in this case may be less so, or more so, for painful sensations elicited by other pathways. This factor rather than some methodological inadequacy may account for our inability to detect analgetic effects of lesser amounts of acetylsalicylic acid than 1.8 gm, whereas a dose which is

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commonly recognized as clinically efficacious is 0.6 gm. Acetylsalicylic acid probably has many sites of action in the central nervous system, since it affects other physiological functions besides perception of pain. Its relief of pain of various kinds may be due to a combination of actions at several neuronal sites. Those which are activated by the dental innervation, which is chiefly of myelinated nerve fibers (3)) may be considerably less sensitive to the drug than are others which may be activated by messages that also include impulses in C fiber afferents. Fortunately, these problems and questions lend themselves to experimental analysis and further work should provide answers. References 1. 2.

BEECHER, H. K. 1959. “Measurement of Subjective Responses.” Press, London and New York. BEECHER, H. K., A. S. KEATS, F. MOSTELLER, and L. LASAGNA.

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problem of placebo “reactors” and “non-reactors.” J. Pharmacol. Exptl. Therap. 109: 393-400. BROOKHART, J. M., W. K. LIVINGSTON, and F. P. HAUGEN. 1953. Functional characteristics of afferent fibers from tooth pulp of cat, J. NeurophysioZ. 16: 634-642. COSTEN, J. B., M. H. CLARE, and G. H. BISHOP. 1951. The transmission of pain impulses via the chorda tympani nerve. Ann. Otol. Rhinol. Laryngol. 50: 591-609. FIASCONARO, J. E., H. SHERMAN, and H. GRUNDFEST. 1957. Determination of clinical dental local anesthesia by electrical stimulation and digital plethysmograph. J. Am. Dental Assoc. 54: 33-43. GOETZL, F. R., D. Y. BURRILL, and A. C. IVY. 1943. A critical analysis of algesimetric methods with suggestions for a useful procedure. Quart. BUZZ. Northwestern Univ. Med. School 17: 280-291. GRUNDFEST, H., J. J. HAY, and S. FEITELBERG. 1945. Strain gage recorder for physiological volume, pressure and deformation measurements. Science 101: 255-256. GRUNDFEST, H. 1957. Electrical inexcitability of synapses and some of its consequences in the central nervous system, PhysioZ. Rev. 37: 337-361. GRUNDFEST, H. 1958. In “Reticular Formation of the Brain,” pp. 473-487. L. D. Proctor, R. S. Knighton, H. H. Jasper, W. C. Noshay, R. T. Costello reds.]. Little, Brown, Boston, Massachusetts. GRUNDFEST, H. 1959. Evolution of conduction in the nervous system, pp. 43-86. In “Evolution of Nervous Control,” A. D. Bass [ed.]. Publ. 52 American Association for the Advancement of Science, Washington. GRUNDFEST, H. 1961. Excitation by hyperpolarizing potentials. A general theory of receptor activities, pp. 326-341. In “Nervous Inhibition,” E. Florey fed.]. Pergamon Press, London.

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12. GRUNDFEST,H. 1963. Evolution of electrophysiological varieties among sensory receptor systems. In “Problems of Evolution of Function and Enzymochemistry of Excitation Processes” (in press). J. W. S. Pringle red.]. Pergamon Press, London. 13. HARDY, J. D., H. G. WOLF, and H. GOODELL. 1952. “Pain Sensations and Reactions.” Williams & Wilkins, Baltimore, Maryland. 14. HARRIS, S. C., and L. E. BLOCKUS. 1952. The reliability and validity of tooth pulp algesimetry. J. Pharmacol. Exptl. Therap. 104: 13.5-148. 1.5. JELLINEK, E. M. 1946. Clinical tests on comparative effectiveness of analgesic drugs. Biometrics 2: 87-91. 16. KRUEGER, H. 1955. Narcotics and analgesics, pp. 2-77. In “The Alkaloids,” Vol. 5, R. H. F. Manske led.]. Academic Press, New York. 17. LANDAU, W., and G. H. BISHOP. 1953. Pain from dermal, periosteal and fascial endings and from inflammation. A.M.A. Arch. Neurol. Psychiat. 69: 490-504. 18. LASAGNA, L., and H. K. BEECHER. 1954. The optimal dose of morphine. J. Am. Med. Assoc. 156: 230-234. 19. L~SACNA, L., F. MOGTELLER, J. M. VON FELSINGER, and H. K. BEECHER. 1954. A study of the placebo response. Am. J. Med. 16: 770-779. 20. ROSEN, S. 1954. Meniere’s Disease: Successful treatment by chorda tympanectomy. A.M.A. Arch. Neurol. Psychiat. 72: 682-687. 21. SHERMAN, H., J. E. FIASCONARO, and H. GRUNDFEST. 19.57. Clinical efficiency of recent local anesthetics. N.Y. State Dental J. 23: 403-413. 22. STRAND, H. A., F. HENNINCER, and J. M. DILLE. 1958. Evaluation of analgesic combinations for dental use. J. Am. Dental Assoc. 66: 491-498. 23. SWEET, W. H. 1959. Pain, pp. 459-506. In “Handbook of Physiology, Sect. I, Vol. 1. J. Field [ed.]. American Physiological Society, Neurophysiology,” Washington. 24. ZIJBIN, J. 1960. Pain. In “Experimental Abnormal Psychology,” Vol. 2, Chapter XIIA. Columbia University Book Store, New York.