Study of Analgesics

Sections

A. Studies of analgesic potency
B. Studies of side action liability
C. Studies of low potency analgesics
D. Studies of analgesia
E. Comparison of local irritant properties of the sulphate and phosphate salts of morphine
F. Study of pre-medication
H. Field trial of methadone and levo-iso-methadone
G. Controlled study of pain relief by intravenous procaine

Details

Author: K. Henry Beecher
Pages: 9 to 15
Creation Date: 1951/01/01

TECHNICAL

Study of Analgesics

M.D. K. Henry Beecher The Anesthesia Laboratory of the Harvard Medical School at the Massachusetts General Hospital, Boston, Massachusetts

This article was transmitted to the Bulletin by Mr. Harry. J. Anslinger, Commissioner of Narcotics, representative of the United States at the Commission on Narcotic Drugs. It is a part of the studies of the National Research Council on the subject of drug addiction and narcotics. It presents various recent studies of analgesic drugs. Of particular interest is the finding (part H) that methadone and levoisomethadone are "at least the equal of morphine in their pain relieving power" and "as dependable as morphine."

This report presents the progress to date in the several aspects of our studies of analgesia and analgesic drugs. Except for the determinations of the analgesic potency of Heptazone, WIN 1161-2, and 6-methyl dihydromorphine, all data included here were collected during the period of the current grant (1 June to 31 December 1950).

A. Studies of analgesic potency

Our method for determining the potency of analgesic drugs in post-operative patients (Denton, J. E., and Beecher, H. K.: New Analgesics. I. Methods in the clinical evaluation of new analgesics, J.A.M.A., 141: 1051-1057, 1949) has been recently published in detail (Keats, A. S., Beecher, H. K., and Mosteller, F. C.: Measurement of pathologic pain in distinction to experimental pain, J. Appl. Physiol., 1: 35-44, 1950). This method has not been modified. We have investigated the use of 5 mg. of morphine per 70 kg. of body weight as the standard analgesic. This dose provided no great advantage over the 10 mg. standard used previously.

Our greater experience with this technic has made possible more rapid and economical determinations of analgesic potency. This improvement has been effected mainly by the use of larger intervals between dose levels. Investigation of a single drug now requires study of only three doselevels. An examination of the accuracy of, determinations based on one or two dose levels is planned.

The dose of the following drugs producing analgesia equivalent to 10 mg./70 kg. of morphine has been determined:

  1. dl 4,4-diphenyl-6-morpholinoheptanone-3-hydrochloride (Heptazone) equivalence to morphine at 60 mg.

  2. 1 3-dimethylamino-1,1-diphenylbutyl ethyl sulfone hydrochloride (WIN 1161-2). Six dose levels of this drug were investigated. The results were chaotic. When the time over which the drug was studied was considered, a decreasing effectiveness with time was suggested. It was our conviction; which we stated at the time these data were obtained, that the drug is unstable. A recent study of the stability of this drug, as yet unpublished (N. B. Eddy: Personal communication) describes the breakdown of this chemical at 120°C. - approximately the sterilizing temperature of our solutions. This could readily account for the erratic behaviour we have observed.

  3. 6-methyl dihydromorphine: Equivalence to morphine at 30 mg.

  4. Methyldihydromorphinone hydrochloride (Metopon): Equivalence at 3.5 mg.

B. Studies of side action liability

Fifteen healthy male students were each given the following drugs subcutaneously:

Saline
1.0 cc./70 kg.
Sodium pentobarbital (intravenously
200 mg./70 kg.
Morphine sulphate
10 mg./70 kg.
Heptazone
60 mg./70 kg
Metopon
3 mg./70 kg.
6-methyl dihydromorphine
30 mg./70 kg.
1-isomethadone
10 mg./70 kg.

Doses which produce equivalent analgesic effect in post-operative patients.

Five days elapsed between successive drug administrations and the order of drugs was different in each subject.

The following measurements were made before and at intervals after each drug administration.

Blood pressure

Pulse

Oral temperature

Resting respiratory rate

Resting minute volume

Resting oxygen consumption

Minute volume response to 5 per cent CO 2

Respiratory rate response to 5 per cent CO 2

The frequency of certain symptoms and signs following each drug were also recorded. This number of subjects is too small to demonstrate any conclusive differences between drugs, but will be expanded to thirty subjects.

No differences were observed between the effect of saline and any of the drugs studied on pulse and blood pressure.

Curves were obtained by converting each measurement to a per cent of its pre-drug value and obtaining a mean per cent of each time interval. For the application of Statistical tests, the data of each measurement for each individual were plotted as per cent of pre-drug value against time. The area between this curve and the baseline (the 100 per cent line) was calculated. This area represented total change from pre-drug value (an expression of both degree and duration of effect). The fifteen areas for each measurement constituted the data for comparison of drugs by the t-test. Morphine was selected as representative of the five narcotics and was compared to saline. The t values indicate the sensitivity of the various measures used to determine the respiratory depressant effects of narcotics.

In order to compare the five narcotics alone and to learn if any one was less depressant than the others, an analysis of variance was done. The data for this analysis were obtained by calculating (from the plotted curves of each individual and for each measurement mentioned above) the area between the drug curve and the individual's own saline curve (instead of the baseline). This area represented total change from the individual's performance after saline or total change attributable to the drug alone. Thus the fifteen areas for each drug and each measurement were compared. In none was significance between drugs obtained. This lack of differences between drugs supports the accuracy of the equivalent analgesic doses determined previously, if analgesia and respiratory depression are fundamentally related.

C. Studies of low potency analgesics

We have adapted our method for measuring analgesia to use in determining the potency of acetyl salicylic acid-like compounds. At present 0.3 gm. of aspirin orally is being compared with a placebo. Selection of postoperative patients without severe pain and the frequent inability of these patients to retain oral medication have been the major problems here. The data collected to date indicate that with carefully selected patients, the potency of such drugs can be measured. This study will continue and will include study of 0.6 gm. of aspirin, codeine and oral morphine.

Here are some sample data:

Subjects: Post-operative patients on the orthopaedic service were studied over some interval between the second and fifth post-operative days (starting when parenteral morphine was no longer required for pain control). Maximum interval of study was forty-eight hours. In most patients all pain disappeared before forty-eight hours of study.

Drugs: Patients were alternately given codeine. "A" (starch capsule; placebo), and codeine "B" (0.3 gm. aspirin in starch) po. q. 2h. prn. for pain only. If no relief after one dose of each, a parenteral narcotic was given and codeine "A" and "B" resumed. Evaluations were made by technicians at one and two hours after medication.

Results: Twenty patients studied to date (including those receiving only one dose of one drug).

 

Codeine "A" (placebo)

Codeine "B" (aspirin)

Total doses
31 36
Analgesic doses
9 22
Per cent relief
29 61

These are crude percentage reliefs, which will be statistically weighted for dose number in final evaluation.

Plans: Code letters have been reversed and the procedure above is being repeated with an additional twenty patients. To establish a dose-effect relationship, 0.6 gm. aspirin (and more if indicated) will be similarly studied.

D. Studies of analgesia

We are investigating the effects of conditioning factors in pain relief from narcotics. We are studying the influence of three doses of saline on the relief of succeeding doses of morphine and the influence of three doses of morphine on the relief of succeeding doses of saline. Thirty patients have been studied in this way. The data are inconclusive as yet, but indicate that conditioning is not a major factor in the acute pain of the immediate post-operative period. This study is continuing.

E. Comparison of local irritant properties of the sulphate and phosphate salts of morphine

Method: Solutions of morphine sulphate and morphine phosphate (10 mg./cc.) were alternately given to individual post-operative patients as necessary for treatment of their pain. The doses used were those prescribed by the surgeon (8 or 10 mg. every three to four hours). All injections were given subcutaneously in the upper arm by the standard nursing technic employed in this hospital. One dose of each morphine salt was given in either the right or left arm, the other arm then being used for the succeeding two doses, etc. The phosphate was given initially as often as was the sulphate. The patients were interviewed and their arms examined by trained technicians before and at thirty and sixty min- utes after each injection, The following observations were made:

  1. Pain relief (See A. S. Keats, H. K. Beecher and F. C. Mosteller. J. Appl. Physiology, 1: 35, 1950).

  2. Induration-circumscribed subcutaneous form swelling or hardness larger than 2-3 cm. in diameter ("can be picked up")-not a wale.

  3. Redness-at site of injection, one centimetre or more.

  4. Tenderness-pain on pressure.

  5. Soreness-aching at site of injection.

  6. Sting on injection.

Results: Patients studied: forty-eight.

 

Sulphate

Phosphate

Total doses
103 106
Doses given for moderate or severe pain
87 87
Analgesic dose
52 56
Per cent relief
59.8 64.4
 

Incidence of:

Lasting less than one hour (percentage)

Lasting more than one hour (percentage)

Lasting less than one hour (percentage)

Lasting more than one hour (percentage)

Induration
3.9 8.7 4.7 11.3
Redness
17.5 36.9 23.6 39.6
Tenderness
4.9 2.9 4.7 2.8
Soreness
2.9 1.0 0.9 0.9
Sting on injection
82.5
 
78.0
 

Conclusion: There is only a suggestion in these data that the phosphate salt of morphine produces more induration and redness than the sulphate. Even if these differences were shown to be real by a more extensive study, their magnitude is hardly of clinical significance.

F. Study of pre-medication

At the present phase of the study three medication solutions have been alternately administered as unknown solutions for a total of 293 anesthetics. These solutions have been prepared in a standard fashion so that in each case a 2 cc. volume contained either:

  1. 15 mg. morphine sulphate and 0.6 mg. atropine sulphate.

  2. 90 mg. pentobarbital sodium and 0.0 mg. atropine sulphate.

  3. 0.6 mg. atropine sulphate.

All pre-medication solutions were administered on the basis of 2 cc. of solution per 70 kg. of body weight. All solutions remained as unknown to the patient, floor nurse, anesthetist, and examiner. This was attained by the use of the following order form:

Full size image: 14 kB

Code numbers were changed at the end of each month. Cases were selected at random, except for patients with known surgical or medical contra-indications to use of the drugs being studied. In addiction both extremes of weight and age were avoided.

The form used for collection of data was as follows:

A STUDY OF PRE-ANESTHETIC MEDICATION Massachusetts General Hospital

Full size image: 66 kB, A STUDY OF PRE-ANESTHETIC MEDICATION Massachusetts General Hospital

CASES STUDIED

A break-down of the anesthetics used was as follows:

Nitrous oxide-ether
167
Cyclopropane
18
Thiopental sodium
24
Thiopental sodium plus gas
24
 
233

The average time from administration of the pre-medication solution until induction of anesthesia was fifty-nine minutes.

The average time from the induction of anesthesia until the blood sample was drawn was fifty-eight minutes, or an average of 117 minutes after the pre-mediation solution had been given to the patient.

INDUCTION OF ANESTHESIA

The anesthetists characterized the induction of anesthesia as follows:

   

Percentage

 

Smooth

Smooth but slow

Difficult

Stormy

Morphine + atropine
63 11 20 6
Pentobarbital + atropine
65 17 12 6
Atropine alone
61 12 22 5

It would appear from the anesthetists' point of view that the average induction was not influenced by the addition of either morphine or pentobarbital to the pre-medicating solution.

TIME REQUIRED FOR INSERTION OF ENDOTRACHEAL TUBE

The endotracheal tube is inserted as soon as relaxation of the jaw is sufficient. This provides a good end point for the induction period. The average time for the insertion of the endotracheal tube was as follows:

 

Minutes

Morphine + atropine
21
Pentobarbital + atropine
19
Atropine alone
18

These figures suggest that the addition of morphine or pentobarbital to the pre-medicating solutions do not expedite induction, but may actually delay the attaining of sufficient depth of anesthesia for this manipulation.

ANESTHETIST'S OPINION OF PRE-MEDICATION

The anesthetists characterized the adequacy of the pre-medication solutions as follows:

 

Percentage

 

Adequate

Inadequate

Excessive

Thought a narcotic used

Morphine + atropine
63 36 1 47
Pentobarbital + atropine
66 32 2 55
Atropine alone
59 39 2 27

These figures suggest that the anesthetists were equally satisfied with all pre-medication solutions including the control solution containing atropine alone. In addition,53 per cent of the anesthetists were actually unaware when morphine had been used in the pre-medicating solution. There was a considerable tendency for the anesthetist to confuse the presence of pentobarbital with morphine. Furthermore, the anesthetist mistakenly thought 27 per cent of the control (atropine) group had been pre-medicated with morphine. All opinions were expressed independent of changes in eye signs.

PATIENT'S PRE-OPERATIVE STATUS

  1. As evaluated by the anesthetist.

  1. The following physical signs were recorded by the anesthetist:

 

Respiratory Rate

Pulse

Blood Pressure

Morphine + atropine
19 82
122/74
Pentobarbital + atropine
19 82
126/73
Atropine alone
20 86
124/70
  1. The patient's mental status was evaluated by the anesthetist as follows:

 

Percentage

 

Discomfort

Apprehension

Excitement

Euphoria

Morphine + atropine
14 54 19 6
Pentobarbital + atropine
8 64 18 5
Atropine alone
15 64 28 7
 

Percentage

 

Depression

Nausea

Talkativeness

Morphine + atropine
15 4 25
Pentobarbital + atropine
12 1 29
Atropine alone
10 10 24

The pentobarbital solution appeared to be most effective in making the patient comfortable pre-operatively, but both morphine and pentobarbital were equally effective in reducing the pre-operative excitement phase.

  1. As evaluated by the patient himself.

  1. The patient was asked a series of direct questions just preceding induction of anesthesia. His response was as follows:

 

Percentage

 

Discomfort

Apprehension

Excitement

Morphine + atropine
5 31 27
Pentobarbital + atropine
5 34 34
Atropine alone
9 43 39
 

Percentage

 

Euphoria

Depression

Nausea

Morphine + atropine
9 20 27
Pentobarbital + atropine
8 18 4
Atropine alone
10 12 5

Both pentobarbital sodium and morphine sulphate appeared to make the patient comfortable pre-operatively. His apprehensive and excited state was somewhat relieved by both morphine and pentobarbital, although perhaps morphine was slightly more effective. This is of questionable significance.12

  1. On his first post-operative day the patient was again asked the same direct questions about his pre-operative period. His response was as follows:

 

Percentage

 

Discomfort

Apprehension

Excitement

Morphine + atropine
5 32 41
Pentobarbital + atropine
3 30 31
Atropine alone
5 37 37
 

Percentage

 

Euphoria

Depression

Nausea

Talkativeness

Morphine + atropine
21 40 6 22
Pentobarbital + atropine
23 38 15 22
Atropine alone
24 36 11 25

These responses follow somewhat the same general trend as shown by the patient's pre-operative questions.

PATIENT'S OPINION OF ANESTHETIC INDUCTION

On the first post-operative day the patients were interviewed as to their opinion of the pleasantness or unpleasantness of the anesthetic induction. Their reaction was as follows:

 

Percentage

 

Pleasant induction

Unpleasant induction

Indifferent induction

Morphine + atropine
69 7 24
Pentobarbital + atropine
68 3 29
Atropine alone
64 9 27

PATIENT'S RECALL OF DETAIL

The patients were interviewed on the first post-operative day and asked to tell what they could recall of the hour just preceding induction of anesthesia. On the basis of a check list, the number of positive responses was as follows:

 

Number of items recalled (4.00 = 100 per cent recall)

Morphine + atropine
3.09
Pentobarbital + atropine
3.05
Atropine alone
3.14

There was apparently little significant difference in the patient's ability to recall details of the pre-operative stages with the drugs and doses studied.

BLOOD ANESTHETIC LEVELS

Venous blood ether levels were determined in thirty-three patients; venous blood cyclopropane levels were determined in eleven patients, so far.

Thiopental sodium in terms of milligrams of drug used per minute of anesthesia was calculated in twenty-two of the twenty-four cases in which that drug was used as the sole anesthetic agent.

   

Percentage

 

Cyclopropane

Ether

Thiopental sodium

Morphine + atropine
15.5 mg 101.8 mg
27.5 mg/min.
Pentobarbital + atropine
16.8 "
100.1 "
37.7 "
Atropine alone
15.0 "
98.2 "
34.8 "

Summary: Pentobarbital appears to be a satisfactory substitute for morphine in pre-anesthetic medication. Indeed, neither morphine nor pentobarbital appear to be very important.

H. Field trial of methadone and levo-iso-methadone

Some thousands of uses of these agents in controlled studies at the Massachusetts General Hospital as well as studies elsewhere made it clear, not only in studies of analgesic power, but also in studies of side effects, that the two best agents, racemic methadone and levo-iso-methadone, were at least as good as morphine and in the latter case, better. However, before any sweeping decisions were made, it appeared desirable to give these agents a field trial. This was done in two types of installation, forward and rear, the Evacuation Hospital at Hamhung, North Korea, and in the Tokyo Army Hospital at Tokyo.

Hamhung data. The agents were rotated mechanically and no tally was made until the study was completed.

A "+" represents satisfactory pain relief both at forty-five minutes and again at ninety minutes.

A " - " represents unsatisfactory) pain relief at one or both forty-five and ninety minutes.

Agents employed and dose

100 mgm. pentobarbital + -

Satisfactory and unsatisfactorydoses
4 - 4
Hamhung per cent relief
50
Large civil trial per cent relief
50

Tokyo data. I am particularly indebted to the Army for the way it facilitated the initiation and maintenance of this project at the Tokyo Army Hospital. It was promptly arranged that three medical officers of the - General Hospital who were on temporary duty at the Tokyo Army Hospital would be transferred to three eight-hour shifts, so this work could be carried out around the clock. The officers concerned were Captain Philip A. Defter, Captain Frank E. Fink, and Captain Daniel B. Sullivan. While these officers were not experienced in research they entered into this study with such enthusiasm and loyalty to the job to be done that they gave a most creditable demonstration of good work. Later on they took on ward duties in addition to these activities. Sergeant Spicer, the pharmacist, was an invaluable aid in carrying out these studies. The technic of an evaluation of this kind requires that all drugs be administered and appraised as unknown agents. Thanks to Sergeant Spicer's help in this regard, the accumulation of these data continued while I was in Korea. Certainly a maximum of work was done in a minimum of time.

Agents employed and dose

15 mgm. racemic methadone + -

15 mgm. 1 - iso methadone + -

15 mgm. morphine + -

1 cc. Normal saline + -

5 mgm. morphine 50 mgm. with pentobarbital + -

100 mgm. pentobarbital + -

Satisfactory and unsatisfactorydoses
9 - 0
9 - 1
7 - 2
2 - 7
9 - 0
4 - 4
Hamhung per cent relief
100 90 78 22 90 50
Large civil trial per cent relief
80 80 80 20
-
50

In the civil trial 10 mgm. per 70 kg. body weight was the dose used for morphine and the two methadones.

To simplify the work in the Tokyo Army Hospital all patients received the same dose, 10 mgm. of narcotic, not as in our civil trial per 70 kg. body weight, but 10 mgm. total dose; in this use in soldiers previously in good physical condition, the discrepancies as to dose and weight cancel out accurately enough for this field trial.

It is clear, whether one looks at the Hamhung sample, at the larger body of Tokyo data, or at the combined data, that either of the two methadones is as effective as morphine in pain relief.

It is not surprising that we obtained a somewhat higher percentage of relief from the saline placebo in the Tokyo Army Hospital than at Hamhung and in our civil experience; as we have pointed out in previous reports, the wounded soldier passes from his first state of euphoria to a depressed, anxious state often found at the general hospital level. At this level the attention inherent in the injection procedure is of more importance than it is to the freshly wounded man. This perhaps is reflected in the higher percentage of pain relief from the placebo·

Summary and conclusions. Two morphine substitutes, methadone and levo-iso-methadone, have been given a field trial at Hamhung, North Korea (within thirty-five miles of the advancing Chinese armies), and at Tokyo Army Hospital. These agents are at least the equal of morphine, milligram per milligram, in their pain relieving power. The sample observations made in the field support the much wider and more rigorously controlled data already accumulated at the Massachusetts General Hospital. The conclusion is supported that these agents are as dependable as morphine and since they can be synthesized quite easily they can free the Surgeon General, as well as the country as a whole, from the necessity for stockpiling morphine. This is of increasing importance as the prospects grow that we shall be cut off from Asiatic and other sources of morphine.

TOKYO ARMY HOSPITAL

Agents employed

10 mgm. racemic methadone + -

10 mgm. 1-iso methadone + -

10 mgm. morphine + -

1 cc. normal saline + -

Tokyo satisfactory and unsatisfactory doses
17 - 3
14 - 5
15 - 4
7 - 13
Tokyo per cent relief
85 74 79 35
Large civil trial per cent relief
80 80 80 20

78 medications in 46 patients

COMBINATION OF TOKYO AND HAMHUNG DATA

Agents employed

10 mgm. racemic methadone + -

10 mgm. 1-iso methadone + -

10 mgm. morphine + -

1 cc. normal saline + -

Combined satisfactory and unsatisfactory doses
26 - 3
23 - 6
22 - 6
9 - 20
Combined per cent relief
90 79 79 31

This combination of data might seem illogical since 10 mgm. doses were used in Tokyo and 15 mgm. doses in Hamhung; however, the lack of any real difference in the two results supports the earlier finding of Denton and Beecher that very nearly the maximum analgesic power of these narcotics is obtained with 10 mgm. doses.

G. Controlled study of pain relief by intravenous procaine

The apparent inconsistency between the rapid breakdown of procaine intravenously and the reported long duration of analgesia resulting from its administration, led to a controlled study of the analgesic potency of this drug. The method was that previously used for the measurement of pain relief from intravenous barbiturates (A. S. Keats and H. K. Beecher: Pain Relief from Barbiturates and a Hypothesis, J. Pharmacol. and Exper. Therap., 100: 1, 1950). A comparison was made between intravenous procaine (with and without added ascorbic acid), saline, and morphine in fifty-two patients. Because of the abundance of side effects following intraveneous procaine, three categories of response were established, viz:

  1. No pain relief.

  2. Pain relief with highly unpleasant and distressing side actions.

  3. Pain relief with minor or no side actions.

The last category only was considered a therapeutic effect and was present in 21 per cent of patients following saline, 38 per cent following procaine, and 79 per cent following morphine. When the side actions were ignored (response 2 and 3), pain relief followed saline in 21 per cent of patients, procaine in 53 per cent, and morphine in 83 per cent. The serious side actions included convulsions, dyspnea, tachycardia, hallucinations and disorientation.

STATISTICAL EVALUATION OF DATA EFFECTS OF MORPHINE COMPARED TO SALINE

Measurement

t value

P

Oral temperature
1.71
0.1 - 0.5
Resting minute volume
2.80
0.01 - 0.02
Resting respiratory rate
3.58 0.01
Resting oxygen consumption
1.40
0.1 - 0.5
5% CO 2 minute volume
5.34 0.01
5% CO 2 respiratory rate
1.28
0.1 - 0.5

Analysis of variance on data of the five morphine-like drugs shows no significant differences in any measurement.