The rate of development of physical dependence and tolerance to analgesic drugs in patients with chronic pain. Comparison of morphine, oxymorphone and anileridine

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METHOD
RESULTS

Details

Author: Nathan B. Eddy, , Lyndon E. Lee, Jr., , Carl A. Harris
Pages: 3 to 17
Creation Date: 1959/01/01

The rate of development of physical dependence and tolerance to analgesic drugs in patients with chronic pain. Comparison of morphine, oxymorphone and anileridine 1

M.D. Nathan B. Eddy,
M.D. Lyndon E. Lee, Jr., 2
M.D. Carl A. Harris3 Section on Analgesics, Laboratory of Chemistry, National Institute of Arthritis and Metabolic Diseases, National Institutes of Health, Department of Health, Education and Welfare, Bethesda, Md.

2Formerly Chief of Surgery, Wayne County General Hospital, Eloise, Michigan. Present address: Veterans Administration, Washington, D.C.

3 Director of Laboratories, Pondville Hospital, Walpole, Massachusetts.


1 This study was supported in part by the Committee on Drug Addiction and Narcotics of the National Research Council from funds contributed by a group of pharmaceutical manufacturers.

Formerly, the general impression from clinical experience was the only means of judging the properties of tolerance and physical dependence liability (addiction liability) of a substance. Under these circumstances many years might elapse before a reasonably accurate appraisal of those properties of a drug was attained. During the past twenty-five years the Addiction Research Center of the United States Public Health Service Hospital at Lexington, Kentucky, has developed new techniques for measuring addiction liability, and has compared the properties of many new drugs with those of morphine and related substances (Eddy, Halbach & Braenden, 1956). The dosage schedules employed and the utilization of post-addicts as the research subjects relate the results at Lexington more directly to liability to abuse than to the outcome of daily clinical experience, but substances found at Lexington to have morphine-like properties, and judged to be addicting, have shown similar properties when they came into clinical use. During the past ten years Seevers and his associates at the University of Michigan have developed other techniques for screening compounds for physical dependence liability using the monkey as the test object.* Their results have proven to be comparable in most instances to the results in man at Lexington and have provided a rapid preliminary judgement, with the added advantage that many more compounds could be handled than at Lexington in the same period of time. The results in post-addicts and in the monkey are most helpful, but it would be still more helpful to know as soon and as clearly as possible the addiction hazard of daily clinical use of analgesic drugs.

An attack upon the question of addiction liability in clinical practice was initiated a little more than twenty years ago under the auspices of the Drug Addiction Committee of the National Research Council (Eddy & Himmelsbach, 1936;Lee, 1942). Selected subjects with chronic pain were given morphine or another comparable analgesic in an amount and at an interval just sufficient to control their pain. At two- or three-week intervals the analgesic was witheld for a period up to twenty- four hours, and careful hour-by-hour observations were made for the appearance of abstinence phenomena. Recurrence of pain was the major difficulty and often made the period of withdrawal so short that no abstinence phenomena could be expected.

* Unpublished results, reported to the Committee on Drug Addiction and Narcotics of the National Research Council.

The production of nalorphine has made possible a new line of attack. Wikler, Fraser & Isbell (1953) showed that nalorphine would precipitate abstinence phenomena in subjects who had received 15 to 30 mg of morphine four times daily for three to seven days, or 10 mg of methadone four times daily for two to five days; or 15 mg of heroin four times daily for two days. Later in the addiction period, with any one of these drugs the same dose of nalorphine would precipitate a more intense abstinence syndrome. Indeed, later, during continued methadone administration, nalorphine precipitated abstinence changes which exceeded in severity those which ensued after abrupt withdrawal of morphine following long periods of addiction to high doses of that drug. These observations implied that physical dependence on morphine-like substances began to develop within a week, perhaps even with the first dose, and increased in intensity with continued administration. However, the results with methadone indicated that the intensity of abstinence signs, precipitated by nalorphine was not necessarily a basis for prediction of the intensity of abstinence which would follow abrupt withdrawal, since withdrawal of methadone was followed by a slowly developing relatively mild abstinence syndrome (Isbell et al., 1948). Nevertheless, if morphine or another morphine-like analgesic were given for chronic pain and if nalorphine were given periodically during such administration in fixed amount and in fixed relation to the last dose of analgesic, followed by observation for characteristic abstinence symptoms, the appearance and intensity of such symptoms could be a measure of the time required for or the rate of development of physical dependence The procedure to be described is based on this hypothesis.

METHOD

Selection of patients

From a population of patients with inoperable cancer,** individuals were selected who had persistent pain of an inten sity to warrant the application of an opiate. Their histories were scanned to select those with little previous narcotic experience and each patient was screened by an initial "allyl test" (see below) to rule out an already existing detectable physical dependence. After the allyl test a suitable patient was started on subcutaneous administration of a coded medication, coded to provide double blind conditions. The patient remained on that coded medication as long as he or she remained under study, avoiding entirely other analgesics and so far as possible other sedatives. (Rarely, thorazine was given to control vomiting.) The analgesic dose was adjusted, if necessary, within the first two or three days to an amount giving satisfactory pain relief. It was repeated only when recurrence of pain demanded repetition and was increased only if pain relief was inadequate.

** Part at Wayne County General Hospital, observed by Dr. Lee; part at Pondville Hospital, observed by Dr. Harris.

Judgement of pain relief and tolerance

With the first dose of coded medication, and with a single dose weekly thereafter, a careful record was kept on a check-off card of the degree of pain at the time of administration and at half-hour intervals until the next analgesic dose was given. This record was kept by a specially trained nurse observer, who also recorded all narcotic medication and assisted in the allyl tests. As described previously (Eddy & Lee, 1958), the categories of pain were given numerical values ranging from four for severe to one for no pain, and a pain relief score was derived by summing the differences between the value for pain present before and that at each half-hour after drugging. The principal role of these pain relief scores was a check on the adequacy of continuing analgesic medication. A diminishing score, with a maintained or increasing individual dose of analgesic, could also be indicative of developing tolerance. The chief criteria for the latter, however, were the size and number of the analgesic doses, summed to show the amount of analgesic required per week.

Physical dependence, the allyl test

The allyl test was performed initially as a screening procedure before the administration of a coded medication was begun and afterwards at two-week intervals, in each instance two hours after a dose of narcotic. Blood pressure, rectal temperature, respiratory rate and pupil size were determined, and immediately afterwards 1.0 mg of nalorphine hydrochloride was injected subcutaneously. At about five-minute intervals up to twenty minutes, blood pressure, temperature and respiratory rate were re-determined and simultaneously the patient was observed for changes in the pupil and other characteristic signs. Unless the symptoms observed were strikingly characteristic or were severely disturbing to the patient, 2.0 mg of nalorphine hydrochloride were injected twenty-five minutes after the first dose and the observations were continued for at least another twenty minutes. In alternate weeks the same procedure was carried out, injecting 0.5 ml of normal saline (" placebo test ") instead of nalorphine. In these tests the observer knew whether nalorphine or saline was injected.

The signs looked for in each test (allyl or placebo) and the numerical values assigned to them are listed in table 8. These are based on the scoring system of Himmelsbach (1939), with some modifications. No limit was placed on the points allowed for respiratory and temperature changes; and abdominal or other cramps, urge to defaecation, and nausea were added to the list of signs to be scored. Blood pressure, respiratory and temperature changes were the maxima observed during each part of a test, comparing in each case with pre-test values. Mydriasis was the observer's judgement under uniform lighting conditions without quantitative measurement. A score (the sum of the values for all signs observed) of 15 or more was judged to be significantly indicative of the presence of some degree of physical dependence provided such a score was contributed to by something more than changes in blood pressure and respiratory rate. This condition or restriction was necessary because lability of blood pressure and respiration might occasionally, under the conditions of an unusual procedure, produce wide non-specific changes. This was seen in some of the placebo tests, even though the attempt was always made to have the patient as quiet, mentally and physically, as possible.

Drugs

Despite our general knowledge of morphine and its ability to develop tolerance and physical dependence, this new procedure demanded its inclusion as the standard. Compared with it were oxymorphone hydrochloride * and anileridine hydrochloride.** Also, if the results were to have practical value, each drug had to be administered from the beginning in equipotent analgesic dose. Lasagna & Beecher (1954) have shown that the optimal analgesic dose of morphine (morphine phosphate) is 10 mg per 70 kg body weight. Wallenstein & Houde (1956) have determined and we have confirmed (Eddy & Lee, 1958) that the dose of oxymorphone hydrochloride equivalent in analgesic effectiveness to 10 mg of morphine sulfate is very close to 1.0 mg (Wallenstein & Houde reported 1.12 mg, Eddy & Lee 1.02 mg). Several investigators have compared anileridine with morphine and pethidine (summarized by Eddy, Halbach & Braenden, 1957) with the conclusion that the dose equivalent to 10 mg of morphine is very close to 25 mg. Solutions were prepared, therefore, containing 10 mg of morphine sulfate, 1.0 mg of oxymorphone hydrochloride or 25 mg of anileridine hydrochloride per 0.5 ml, and the starting dose for each patient was 0.5 ml per 60 kg of body weight.

To make the procedure double blind and randomize drug administration from patient to patient, each drug solution was supplied to the investigators under five code letters - morphine, E, G, J, L, and O; oxymorphone, A, C, F, M and N; anileridine B, D, H, K and P. Coded drugs were assigned to successive patients in alphabetic sequence. Administration was subcutaneous.

Oxymorphone (INN) is 14-hydroxydihydromorphinone, Numorphan .® It was supplied to us in multiple dose vials, 1.0 mg of the hydrochloride per 0.5 ml by Endo Products, Inc., through the courtesy of Dr. M.J. Lewenstein.

Anileridine (INN) is ethyl 1-(p-aminophenylethyl)-4-phenyl-4-piperidine-carboxylate, Leritine.® It was supplied to us in multiple dose vials, 25 mg of the hydrochoride per 0.5 ml by Merck Sharp & Dohme through the courtesy of Dr. Frederick K. Heath.

Morphine sulfate in multiple dose vials, 10 mg per 0.5 ml, was supplied by Endo Products, Inc., and Merck Sharp & Dohme.

RESULTS

Adequacy of pain relief

Although the starting dose of each drug solution was 0.5 ml per 60 kg body weight, adjustment of the dose was made, if necessary, during the first few days to ensure adequate relief. As a check on the initial adequacy of the three analgesics and the equipotence of the respective concentrations employed, the first five days of drug administration for all patients who received a coded medication for at least two weeks are shown in tables 1, 2 and 3. The variation from patient to patient is a variation according to body weight; the variation from day to day reflects judgement of the adequacy of pain relief. In the last column in each table the dose which appeared to be sufficient for a particular patient has been converted to the dose in mg per 60 kg of body weight. This dose did not vary from the previously accepted equipotent dosage by more than 25% in 68.4% of the patients who received morphine, in 62.5% of the patients who received oxymorphone, and in 76.4% of the patients who received anileridine. This would seem to be a, reasonable confirmation of the equipotency of the solutions used.

The dose of each drug was adjusted as necessary throughout the study to maintain reasonable comfort. A tabulation of the week-to-week pain relief scores (table 4) indicates that this was always accomplished.

TABLE 1

Initial adjustment of analgesic dose

Morphine sulfate, 0.5 ml = 10 mg

Patient

1st day

2nd day

3rd day

4th day

5th day

Effective dose (mg per 60 kg)

L. R,
4x0.40 *
2x0.40
2x0.40
3x0.40
3x0.40
10
A. R.
2x0.28
2x0.28
3x0.28
1x0.28
1x0.28
10
L. S.
2 x0.80
4 x0.80
4 x0.80
5x0.80
5x0.80
10
R. P.
2x0.56
4x0.56
4x0.56
6x0.56
6x0.56
10
M. B.
2x0.48
6x0.40
6x0.40
6x0.57
6x0.481
10
F. M.
2x0.58
2x0.58
5x0.58
4x0.58
1x0.69
10
W. M.
2x0.47
3x0.47
4x0.47
2x0.47
1x0.47
10
H. D.
4x0.47+2 x0.56
2x0.56+3x0.62
6x0.62
4x0.62+2x0.74
6x0.74
16
====
 
 
 
 
 
 
H. C.
2 x0.67
3x0.67+3X0.89
5x0.89
5x0.89
6x0.89
13.3
B. B.
2x0.47
5x0.47
5x0.48
5x0.58
2x0.58+3x0.702
10-15
A. F
4x0.43
6x0.43
5x0.43
6x0.43
2x0,52+3x0.55
10
D. W.
1x0.39
3x0.39
3x0.39
3x0.39
3x0.39
10
F. V.
2x0.50+1x0.63
2x0.63+4x0.83
5x0.83
5x0.83
5x0.83
16.6
E. L.
lx0.43+lx0.52
5x0.52
4x0.52
4x0.52
3x0.52
12
G. H.
1x0.54+2x0.82
6x0.82
4x0.82
5x0.82
4x0.82
15
C. S.
4x0.48
5x0.48
3x0.48+2x0.57
5x0.57
5x0.57
12
K. M.
2x0.56
4x0.56+2x0.67
5x0.67
6x0.67
3x0.67+2x0.84
12
J. F.
2x0.28
2x0.28+2x0.36
6x0.36
5x0.36
5x0.36
12.8
R. G.
1x0.74+2x0.86+2x1.45
3x0.86+2x1.09
5x1.45
5x1.45
5x1.453
20

* Number of doses per day, and individual dose in ml. A day is midnight to Midnight; first day always incomplete, because of irregular time of starting coded medication.

1Continued at this level for 10 days.

2Increased rapidy, during second week to 1.0, held at that level for two weeks and then decreased again to 0.89 for remainder of study

3Dose was decreased to 1.34 in second week, to 1.28 in third week, and increased again to 1.60 in fourth week, continuing at that level.

NOTE.- In this and all succeeding tables, or sections of tables, data on patients above double cross line were obtained at Wayne County General Hospital; on those below it at Pondville Hospital

TABLE 2

Initial adjustment of analgesic dose

Oxymorphone hydrochloride, 0.5ml = 1.0 mg

Patient

1st day

2nd day

3rd day

4th day

5th day

Effective dose (mg per 60 kg)

R.H.
2x0.54 *
4x0.54
2x0.54
4x0.54
4x0.54
1.0
A. Mc.
2x0.57
3x0.57
2x0.57
2x0.57
2x0.57
1.0
F. R.
3x0.37
6x0.37
6x0.37
6x0.45
6x0.451
1.2
S. R.
2x0.40
6x0.40
6x0.40
2x0.40+3 x0.48
6x0.482
1.2
L. W.
2x0.46
4x0.46
3x0.46
6x0.46
4x0.46
1.0
====
 
 
 
 
 
 
A. S.
1x1.35+3x0.43
4x0.43
6x0.43
3x0.53+2 x0.71
5x0.711
2.0
F. K.
4x0.62
5x0.62
5x0.62
4x0.62
2x0.62
1.0
H. Y.
1x0.41
3x0.41
1x0.41+2x0.55
1x0.55
3x0.55
1.33
L. G.
2x0.60+1 x0.48
4x0.48
3x0.48
3 x0.48
5x0.48
0.8
D. R.
1x0.44+3 x0.53
6x0.53
2x0.53+3x0.67
6x0.67
6x0.67
1.5
F. F.
2x0.48
5x0.48
1x048+4x0.60
5x0.60
5x0.60
1.25
S. J.
1x0.39
6x0.39
6x0.39
5x0.39
3x0.39+3 x0.47
1.0
F. O.
4x0.47
2x0.47+4 x0.58
3x0.58+1 x0.70+3x0.38
3x0.88+4 x l.17
6x1.173
2.5
R. W.
2X0.40
3x0.40+1x0.48+2x0.61
5x0.61
5x0.61
5 x0.61
1.5
R. P.
1x0.53
2x0.53+3x0.64
3x0.64+2x1.06
4xl.06
4xl.06
2.0
A. S.
1x0.51
4x0.51
3x0.51+2x0.62
6x0.62
5x0.62
1.2

* Number of doses per day and individual dose in ml. A day is midnight to midnight, first day always incomplete because of irregular time of starting coded medication.

1Continued at this level through two weeks.

2Continued at this level through five weeks.

3Continued through two weeks and then decreased.

TABLE 3

Initial adjustment of analgesic dose

Anileridine hydrochloride 0.5 ml = 25 mg

Patient

1 st day

2nd day

3rd day

4th day

5th day

Effective dose (mg per 60 kg)

H. B
3x0.34*
1x0.34
1x0.34
2x0.34
2x0.34
25
J. S
3 x0.34
3 x0.34
3 x0.34
3 x0.34
3 x0.34
25
J. H
2 x0.57
2x0.57+2x0.68
4 x0.68
4x0.68
4 x0.68
30
J. M
1 x0.54
4 x0.54
4 x0.54
2x0.54
3 x0.54
25
W. H
2 x0.44
5 x0.44
3 x0.44+2 x0.53
6 x0.53
5 x0.53
30
====
 
 
 
 
 
 
E. C
2 x0.48
5 x0.48
2 x0.48
3 x0.48
3 x0.48
25
N. B
1 x0.50
4 x0.50
5 x0.50
3 x0.50+2 x0.60
5 x0.601
25-30
F. M
4 x0.42
3 x0.42
4 x0.42
4 x0.42
1 x0.42+3 x0.562
25-33
P. M
3 x0.77
3 x 0.77+2 x0.96
6 x0.96
5 x0.96
5 x0.96
31
W. N
4 x0.57
4 x0.57
2 x0.57
3 x0.57
5 x0.57
25
P. P
4 x0.34
3 x0.34
3 x0.34
3 x0.23
4 x0.34
25
F. M
3x0.43
3x0.43
1 x0.43
2x0.43
3x0.43
25
F. L
3x0.40
3 x0.40
4 x0.40
3 x0.40+2 x0.50
4 x0.502
25-31
E. P
2 x0.50+2x0.75
3 x0.75+2xl.00
3x1.00
4 x1.00
4 x1.00
50
J. C
2x0.57
3 x0.57+2 x0.73
5 x0.73
4 x0.73
5 x0.73
32
J. M
4x0.90
6x0.90
5 x0.90
5 x0.90
5 x0.90
25
M. F
1 x0.37+3 x0.49
3x0.49+3 x0.61
5 x0.61
6 x0.61
5 x0.61
41

* Number of doses per day and individual dose in ml. A day is midnight to midnight; first day always incomplete because of irregular time of starting coded medication.

1Continued at this level through three weeks.

2Continued at this level through two weeks.

Tolerance

Tables 5, 6 and 7 present a record of narcotic administration for each patient: (1) the initial dose - i.e., the first dose or the dose as adjusted within the first few days for adequate relief; (2) the total amount of narcotic administered to each patient each week; and (3) the final individual dose for each patient. All amounts are given in millilitres to facilitate direct comparison of narcotic need or increases in narcotic medication, since equipotent drug concentrations were used.

Increase in individual dose and probably even more increase in the amount of narcotic used per day reflected developing tolerance, except as advancing disease increased pain intensity in these mainly terminal cases. The reason for discontinuing medication might throw some light on this complicating factor and has been indicated in the last column of each of the three tables under consideration.

Tolerance was considered to be definitely evident in 12 of 16 cases receiving oxymorphone, in 9 of 17 cases on anileridine, and in 9 of 19 cases on morphine. There was a greater difference in the average increase in the individual dose and in the weekly consumption of each narcotic. The final individual dose (average of all cases) was increased by 55.2%, 46.5% and 33.3% with oxymorphone, anileridine and morphine, respectively. Considering only those cases whose coded narcotic administration continued through four weeks or more, the average percentage increase in individual dose at the end of four weeks was 55.2 for oxymorphone, 54.7 for anileridine, and 20.9 for morphine. For the same cases the narcotic consumption was on the average 78.9% greater in the fourth than in the first week for oxymorphone, 54.3% greater for anileridine and 26.0% greater for morphine. In other words, in this series of observations, when narcotic administration was adjusted closely to pain need, there seemed to be less tolerance to the analgesic effect of morphine than to that of oxymorphone or anileridine.

Table 4

Pain relief scores

   

Weeks

Patient

Initial

1

2

3

4

5

6

7

8

9

10

11

12

 
 
 
 
 
 
 
Morphine sulfate
 
 
 
 
 
 
L. R.
21
21+
 
 
 
 
 
 
 
 
 
 
 
A. R. .
9 7 5
 
 
 
 
 
 
 
 
 
 
L. S.
18 20 13
 
 
 
 
 
 
 
 
 
 
R. P.
12 16 13 18 15 12
23+
 
 
 
 
 
 
M. B. .
20 12 7 9 13
21+
14 8
 
 
 
 
 
F. M.
10
19+
16+
 
23+
18+
19+
16+
22+
22 21 20
 
W. M. .
16+
21+
5
 
20 12
21+
19+
 
 
 
 
 
H. D.
22+
14 16 13 8
 
 
 
 
 
 
 
 
H. C.
22+
17
22+
20
 
 
 
 
 
 
 
 
 
B. B.
18+
17+
21+
18
21+
18
21+
24+
21+
 
 
 
 
A. F.
19 19 14 19
 
 
 
 
 
 
 
 
 
D. W.
15 8 19
21+
19
19+
18
 
 
 
 
 
 
F. V.
24+
23+
22+
24+
24+
 
 
 
 
 
 
 
 
E. L.
22
23+
24+
 
 
 
 
 
 
 
 
 
 
C. H.
13 12
14+
 
 
 
 
 
 
 
 
 
 
C. S.
13
 
 
 
 
 
 
 
 
 
 
 
 
K. M.
20 20 16 19 20 20
 
 
 
 
 
 
 
J. F.
19 15
24+
20 12 12 11 14 21
 
 
 
 
R. G.
15 20 20 22 17 16 14
 
 
 
 
 
 
 
 
 
 
 
 
Oxymorphone hydrochloride
 
 
 
 
 
 
 
R. H.
18+
13 16 16 16 13 11
 
 
 
 
 
 
A. Mc.
8
19+
21+
21 12 15
24+
14 13 14 19 13 15
F. R.
14 12 10
 
9
 
11 10 14 14 5 18 14
S. R.
4 19 5 7 12 16
 
 
 
 
 
 
 
L. W.
12 16 15
19+
20+
 
 
 
 
 
 
 
 
A. S.
17
18+
22+
19
 
 
 
 
 
 
 
 
 
F. K.
16 17 20 17 19 14 20 15
16+
20
 
 
 
H. Y.
24+
22
22+
23+
20+
21
 
 
 
 
 
 
 
L. G.
24+
22 23
23+
17 15 20 17 16 17 21
 
 
D. R.
21
22+
 
 
 
 
 
 
 
 
 
 
 
F. F.
15 17
 
 
 
 
 
 
 
 
 
 
 
S. J.
15
55+
22 22
 
 
 
 
 
 
 
 
 
F. O.
22 20 18
 
 
 
 
 
 
 
 
 
 
R. W.
7 19 12 18 5
 
 
 
 
 
 
 
 
R. P.
20 22 17 20
 
 
 
 
 
 
 
 
 
A. S.
18
19+
23+
20 17
23+
13
 
 
 
 
 
 
 
 
 
 
 
 
Anileridine hydrochloride
 
 
 
 
 
 
 
H. B.
16
21+
13 8 19
16+
15
16+
15
17+
18+
12
15+
J. S.
6 17 21
 
17+
15+
14 11 13 15
 
 
 
J. H.
11 16 15
22+
22
 
 
 
 
 
 
 
 
J. M.
18
 
16+
 
 
 
 
 
 
 
 
 
 
W. H.
16+
17 12 15
 
 
 
 
 
 
 
 
 
E. C.
19+
8 0 13
 
 
 
 
 
 
 
 
 
N. B.
13
24+
22
 
 
 
 
 
 
 
 
 
 
F. M.
22+
14+
 
 
 
 
 
 
 
 
 
 
 
R. Mc.
22 21 21
24+
22 21
 
 
 
 
 
 
 
W. N.
13 15 22 15 14 12 12
20+
24+
22+
 
 
 
P. P.
23+
20 20 15 15
19+
 
 
 
 
 
 
 
F. M.
18 21 15 18 15 20 6 17 20
 
 
 
 
F. L.
22 19
 
 
 
 
 
 
 
 
 
 
 
E. P.
20 20 19 15 16 12
 
 
 
 
 
 
 
J. C.
22 16
 
 
 
 
 
 
 
 
 
 
 
J. M.
13
23+
 
 
 
 
 
 
 
 
 
 
 
M. F.
14 23 19 19
 
 
 
 
 
 
 
 
 
Average
16.8 18.0 16.6 17.9 16.5
 
 
 
 
 
 
 
 

* A + indicates that the record was incomlete; observations were terminated before pain returned to the level at the time of drugging

TABLE 5 - Narcotic administration

Result of the analysis

 

Individual dose**

Weeks

     

Patient

Initially

At end of 4th week

Finally

1

2

3

4

5

6

7

8

9

10

11

12

Tolerance

Reason for dis-continuing coded medi-cation

 
L. R.
0.40
 
0.46 7.44 5.98
 
 
 
 
 
 
 
 
 
 
 
Doubtful
Poor condition
A. R.
0.28
 
0.40 3.92 9.80
 
 
 
 
 
 
 
 
 
 
 
Definite
1
L. S.
0.80
 
0.80 28.00 33.60
 
33.60
 
 
 
 
 
 
 
 
 
None
Died
R. P.
0.56 0.56 0.56 20.26 22.84
 
23.52 23.52 23.52 23.522
 
 
 
 
 
 
None
 
M. B.
0.48 0.68 0.82 17.82 19.52
 
22.95 27.57 28.98 34.44 34.44 34.44
 
 
 
 
Definite
2
F. M.
0.58 0.75 0.75 15.06 20.86
 
21.00 19.50 19.50 17.25 15.00 15.75 19.50 21.00 21.00 21.00
Definite
2
W. M.
0.47 0.47 0.47 7.05 9.88
 
14.00 11.41 12.72 12.69 12.22 6.11 7.52 7.52
 
 
None
Near terminal
H. D.
0.74 0.90 0.70 26.92 29.32
 
28.88 37.92 39.20 39.20
 
 
 
 
 
 
Probable
2
H. C.
0.89 0.69 0.693 36.02 39.96
 
34.13 21.76
 
 
 
 
 
 
 
 
Doubtful
Discharged, home
B. B.
0.70 1.00 0.89 20.71 27.62
 
29.00 23.32 27.06 18.69 21.36
 
 
 
 
 
Probable
" "
A. F.
0.43 0.73 0.73 17.34 22.69
 
25.55 25.00
 
 
 
 
 
 
 
 
Definite
2
D. W.
0.39 0.97 1.43 9.58 21.37
 
27.16 36.86 41.64 54.34
 
 
 
 
 
 
Definite
2
F. V.
0.83 0.37 0.31 27.79 15.60
 
16.00 13.29 9.73
 
 
 
 
 
 
 
None
Discharged, home
E. L.
0.52 0.52 15.08 14.04 12.48
 
 
 
 
 
 
 
 
 
 
 
None
" "
C. H.
0.82 1.09 26.10 34.12
 
 
 
 
 
 
 
 
 
 
 
 
Definite
Poor condition
C. S.
0.57
 
0.57 18.87 15.39
 
 
 
 
 
 
 
 
 
 
 
None
" "
K. M.
0.67 1.12 1.34 28.08 31.92
 
29.40 34.21 44.34 42.88
 
 
 
 
 
 
Definite
2
J. F.
0.36 0.71 1.21 13.80 24.85
 
22.72 23.43 25.13 32.60 40.33 42.35 39.93 38.72
 
 
Definite
2
R. G.
1.45 1.60 1.60 43.61 42.88
 
41.60 47.36 56.00 56.00
 
 
 
 
 
 
Definite
Discharged, home
Average
0.63
 
0.81 20.18 23.28
 
25.47 26.55
 
 
 
 
 
 
 
 
 
 
Average ***
0.66 0.81
 
21.85 25.33
 
25.84 26.55
 
 
 
 
 
 
 
 
 
 
Percentage increase
 
22.7 28.6
 
 
 
 
21.5
 
 
 
 
 
 
 
 
 
 

*All amounts are in millilitres, 0.5 ml. = 10 mg.

**Initially the first dose or the dose as adjusted within the first few days for adequate relief. See table 1

***Average for those patients only who received coded medication for four weeks or more.

1Condition found not to be neoplastic disease.

2Physical dependence demonstrated.

3Maximal individual dose was 1.11 ml. in second week; later reduced below that required initially on account of decreased pain.

TABLE 6 - Narcotic administration

Oxymorphone hydrochlorlde

 

Individual dose **

Total adminis-tration (weeks)

   

Patient

Initially

At end of 4th week

Finally

1

2

3

4

5

6

7

8

9

10

11

12

Tolerance

Reason for dis-continuing coded medi-cation

R. H.
0.54 0.76 0.76 13.46 17.92 26.52 23.60 28.88 29.64 23.22
 
 
 
 
 
Definite
Died
A. Mc
0.57 0.57 0.80 9.12 11.40 13.11 16.53 10.26 21.81 22.68 22.65 24.57 24.08 20.30 22.90
Definite
Near terminal
F. R.
0.45 0.67 0.80 17.49 14.17 24.88 27.47 26.13 26.80 26.80 29.12 29.40 32.60 42.00 44.90
Definite
Died
S. R.
0.48 0.58 0.83 19.48 19.44 24.87 30.05 34.93 38.07
 
 
 
 
 
 
Definite
1
L. W.
0.46 0.50 0.50 13.90 17.80 21.36 19.88 17.50
 
 
 
 
 
 
 
Probable
Died
A. S.
0.71 1.06 1.06 18.86 31.17 40.28 37.10
 
 
 
 
 
 
 
 
Definite
Discharged, home
F. K.
0.62 0.74 1.19 16.12 23.56 26.60 28.20 32.24 42.97 40.90 38.83 37.60 38.03
 
 
Definite
1
H. Y.
0.55 0.68 0.52 10.57 14.96 16.32 15.64 18.08 14.56
 
 
 
 
 
 
Doubtful
Discharged home
F. F.
0.60
 
1.00 19.44 36.30
 
 
 
 
 
 
 
 
 
 
Definite
Poor condition
S. J.
0.39 0.95 0.95 15.90 24.32 36.19 36.20
 
 
 
 
 
 
 
 
Definite
1
F. O.
1.17
 
0.882 36.26 26.33 33.44
 
 
 
 
 
 
 
 
 
None
Died
R. W.
0.61 2.03 2.03 21.56 38.78 51.80 53.91
 
 
 
 
 
 
 
 
Definite
1
R. P.
1.06 1.60 1.60 30.34 47.82 49.53 59.76
 
 
 
 
 
 
 
 
Definite
Discharged, home
A. S.
0.62 0.95 1.42 22.13 26.95 28.49 30.68 34.20 41.59
 
 
 
 
 
 
Definite
1
Average
0.62
 
1.01 18.76 24.41 29.16 30.39
 
 
 
 
 
 
 
 
 
 
Average ***
0.58 0.90
 
16.98 23.32 28.86 30.39
 
 
 
 
 
 
 
 
 
 
Percentage increase
 
55.2 62.9 62.9
 
79.0
 
 
 
 
 
 
 
 
 
 
 

*All amounts are in millilitres, 0.5 ml. = 10 mg.

**Initially the first dose or the dose as adjusted within the first few days for adequate relief. See table 2

***Average for those patients only who received coded medication for four weeks or more.

1Physical dependence demonstrated.

2Condition found not to be neoplastic disease, transferred to another institution.

TABLE 7 - Narcotic administration

Anileridine hydrochloride

 

Individual dose **

Total adminis-tration (weeks)

   

Patient

Initially

At end of 4th week

Finally

1

2

3

4

5

6

7

8

9

10

11

12

Tolerance

Reason for dis-continuing coded medi-cation

H. B.
0.34 0.68 0.68 5.04 3.37 5.04 12.53 17.00 13.60 17.68 21.12 24.48 19.72 18.36 15.64
Definite
Near terminal
J. S.
0.34 0.34 0.34 7.48 7.14 7.48 10.54 9.86 12.58 13.94 14.24 14.28
 
 
 
Doubtful
Died
J. H.
0.68 0.83 0.83 16.32 19.36 21.37 21.58
 
 
 
 
 
 
 
 
Probable
No reason GIVEN
J. M.
0.54
 
0.54 9.27 14.04 12.42
 
 
 
 
 
 
 
 
 
Doubtful
Died
W. H.
0.53 0.83 0.83 16.90 25.50 28.44 31.34
 
 
 
 
 
 
 
 
Definite
1
E. C.
0.48 0.68 0.68 11.04 17.61 19.50 19.04
 
 
 
 
 
 
 
 
Definite.
2
N. B.
0.50 0.92 0.92 18.60 23.40 26.68 32.20
 
 
 
 
 
 
 
 
Definite
Died
F. M.
0.42
 
0.63 11.86 15.26
 
 
 
 
 
 
 
 
 
 
Doubtful
Died
R. Mc.
0.96 1.35 1.35 31.50 35.36 47.60 40.98 47.25 47.25
 
 
 
 
 
 
Definit
1
W. N.
0.57 0.82 1.11 14.82 18.92 24.32 21.32 23.78 22.14 20.63 23.41 22.20
 
 
 
Definite
Died
P. P.
0.34 0.66 0.66 8.50 8.16 15.44 23.82
 
 
 
 
 
 
 
 
Definite
1
F. M.
0.43 1.04 1.32 8.69 12.32 13.28 18.24 27.56 28.18 29.44 33.00 27.72
 
 
 
Definite
Discharged, home
F. L.
0.50
 
0.50 10.20 10.50
 
 
 
 
 
 
 
 
 
 
None
Died
E. P.
1.00 1.00 1.19 24.75 26.00 22.75 31.25 33.00 35.17
 
 
 
 
 
 
Probable
1
J. C.
0.73
 
1.23 24.08 38.41 40.59
 
 
 
 
 
 
 
 
 
Definite
1
J. M.
0.90
 
0.90 26.16 31.50
 
 
 
 
 
 
 
 
 
 
None
Died
M. F.
0.61 0.73 0.73 21.00 23.51 24.82 23.27
 
 
 
 
 
 
 
 
Doubtful
1
Average
0.58
 
0.85 15.66 19.43 22.12 23.84
 
 
 
 
 
 
 
 
 
 
Average ***
0.57 0.82
 
15.39 18.39 21.39 23.84
 
 
 
 
 
 
 
 
 
 
Percentage increase
 
43.9 46.6
 
 
 
54.9
 
 
 
 
 
 
 
 
 
 

*All amounts are in millilitres; 0.5 ml = 25.0 mg.

**Initially the first dose or the dose as adjusted within the first few days for adequate relief. See table 3

***Average for those patients only who received coded medication for four weeks or more.

1Physical dependence demonstrated.

2Condition found not to be neoplastic disease.

Physical dependence

The signs indicative of physical dependence (abstinence signs) or rather the numerical values for these signs (see table 8) for each patient and each allyl test are presented in tables 9, 10 and 11. Under the heading "Initial screening test" are given the scores for all patients tested, whether or not coded medication continued long enough for a second allyl test to be given. Table 12 summarizes the allyl test scores per patient and per test, and includes only those patients on whom at least one test was performed after the beginning of coded medication. For comparison, the results of placebo tests are summarized in table 13.

One hundred and thirty-eight placebo tests were done in the course of this study; one only on 56 patients, two on each of 36 patients, and more than two on smaller numbers. The point scores for the placebo tests were low (average 5.2) and were derived almost entirely from changes in blood pressure, temperature and respiration. The few scores which were 12 or more are shown in detail in the lower part of the table. Of the signs other than blood pressure, temperature or respiratory rate change, goose flesh was noted 14 times, sweating 6 times and lacrimation once.

Initial allyl screening tests were carried out on 27 patients at Wayne and on 51 patients at Pondville Hospital. Definite physical dependence was detected in five cases. Ten other patients at Wayne and 21 others at Pondville were discontinued within the first two weeks for generally poor condition, uncooperativeness or some other cause. Seventeen were continued on morphine sulfate, 14 on oxymorphone hydrochloride, and 16 on anileridine hydrochloride for periods of two to twelve weeks and received one or more allyl tests during that time. One of the morphine cases must be excluded because physical dependence was already present at the time of the screening allyl test.

TABLE 8

Criteria for physical depence

Abstinence signs

Symbol

Numerical value

Systolic blood pressure
BP
1 point for each 2 mm Hg maximal rise, total not to exceed 10 points
Rectal temperature
T
1 point for each 0.1° rise
Respiratory rate
R
1 point for each respiration per minute increase
Yawning
Y
1 point
Lacrimation
La
1 point
Rhinorrhea
Rh
1 point
Sweating
S
1 point
Goose flesh
G
3 points
Mydriasis
My
3 points
Tremor
Tr
3 points
Restlessness
Re
5 points
Abdominal or other cramps
C
5 points
Urge to defecation
D
5 points
Nausea
Na
3 points
Emesis
V
5 points for each act of emesis

Definite physical dependence was demonstrated at some period in all but five patients given multiple allyl tests one who received morphine, two who received oxymorphone, and two who received anileridine. In all these negatives, the period of narcotic administration was brief. Physical dependence was apparent after two weeks of drug administration in 11 of 16 cases when the narcotic was morphine; in 5 of 14 cases when the narcotic was oxymorphone; and in 6 of 16 cases when the narcotic was anileridine. Physical dependence was demonstrable at the end of four weeks in two additional cases and probable in another on morphine; in three additional, probable in another, on oxymorphone; and in five additional, probable in another, on anileridine. Of the ten patients who continued on morphine for six weeks, all must be considered to have developed some physical dependence within that time; of the seven patients who received oxymorphone for six weeks or longer, two were doubtful as to physical dependence at the end of six weeks and one was doubtful in the eighth week (see footnote 5 to table 12); and of the six cases on anileridine for six weeks or more, one was negative for physical dependence in the sixth, but strongly positive in the eighth week. These facts seem to indicate that the development of physical dependence was slightly faster with morphine than with either of the other drugs.

These differences between the drugs were reflected in part and perhaps might in part be accounted for by the total amount of narcotic administered per week; but two facts must be kept in mind: the individual dose was based on body weight, and total narcotic consumption was related to pain need. Of the 16 patients on morphine, 12 received more than 20 ml of morphine solution in the second week, and 9 of these were considered to have some physical dependence at the end of that time. Of the 14 patients on oxymorphone, 7 received more than 20 ml of oxymorphone solution in the second week and 4 of these were considered to be physically dependent at the end of that time. Of the 16 patients on anileridine, 6 received more than 20 ml of anileridine solution in the second week, and 3 of these were considered to be dependent at the end of that time. In the main the patients receiving the greatest amount of narcotic were the ones who showed physical dependence, but there were patients on each drug receiving large amounts who had not yet developed physical dependence (that is, in the second week) at least as demonstrable by the allyl test.

There appeared to be no tolerance to the analgesic effect of morphine in six patients i.e., within the period of observation. Nevertheless, physical dependence became definite in five of these cases, and the sixth received morphine for only two weeks. Patient R. P. is noteworthy in this connexion. His initial dose was 0.56 ml of morphine solution. The dose continued the same throughout. From the middle of the second to the middle of the seventh week, when the study was discontinued, administration was by the clock seven times a day. His pain scores indicated continuous good relief. His allyl test scores after the 1.0 and 2.0 mg doses of nalorphine were 1/0 initially, 3/23 in the second, 6/36 in the fourth and 27/61 in the sixth week, marked physical dependence with no apparent tolerance. Physical dependence without apparent tolerance was seen in one patient who received oxymorphone (patient F. O.) and in one who received anileridine (patient F. L.). The non-tolerant morphine patients who developed physical dependence had received their drug for three to ten weeks; the other non-tolerant physically dependent cases had been drugged for three and two weeks only.

TABLE 9 - Ally test point scores

Narcotic medication = Morphine sulfate

 

Abstinence signs*

 

Patient

BP

T

R

Y

La

Rh

S

G

My

Tr

Re

C

D

Na

V

Total scores

 
 
 
 
 
 
 
Initial screening test
 
 
 
 
 
 
 
 
 
J. P.
0/7
 
 
 
 
 
1/1
0/3
 
 
 
 
 
 
 
1/11 **
L. R.
2/2
2/2
 
 
 
 
 
 
 
 
 
 
 
 
 
4/4 **
A. R.
4/0
 
8/6
 
 
 
 
 
 
 
 
 
 
 
 
12/6
L. S.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0/0
R. P.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0/0
D. L.
2/4
 
2/2
 
 
 
 
0/3
 
 
 
 
 
 
 
4/9 **
B. P.
 
 
4/6
 
 
 
 
 
 
 
0/5
 
 
 
 
4/11 **
M. B.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0/0
F. M.
3/6
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3/6
W. M.
1/1
 
2/4
 
 
 
 
 
 
 
 
 
 
 
 
3/5
H. D.
2/5
 
0/6
 
 
 
 
 
 
 
 
 
 
 
 
2/11
H. C.
 
 
3/0
 
 
 
 
 
3/3
 
 
 
 
 
 
6/3
B. B.
 
 
4/6
 
 
 
 
 
3/3
 
 
 
 
 
 
7/9
M. M.
0/1
1/2
 
 
 
 
 
 
 
 
 
 
 
 
 
1/3**
A. F.
9/10
 
0/10
 
 
 
 
 
 
 
 
 
 
 
 
9/20
D. W.
 
2/3
 
 
 
 
 
 
 
 
 
 
 
 
 
2/3
F. V.
3/7
5/7
2/2
 
 
 
 
 
0/3
 
 
 
 
 
 
10/19
C. H.
4/4
1/1
0/2
 
 
 
 
 
 
 
 
 
 
 
 
5/7
E. L
1/1
1/0
2/2
 
 
 
 
0/3
 
 
 
 
 
 
 
4/6
C. S.
1/7
1/3
0/6
 
 
 
 
 
 
 
 
 
 
 
 
2/16 **
K. M.
 
 
 
 
 
1/1
 
 
 
 
 
 
 
 
 
1/1
J. H.
2/2
1/1
0/2
 
 
 
 
 
 
 
 
 
 
 
 
3/5 **
M. H.
0/5
 
0/6
 
 
 
 
 
0/3
 
 
 
 
 
 
0/14 **
J. F.
2/5
1/4
 
 
 
 
 
 
 
 
 
 
 
 
 
3/9
A. Mc.
5/4
1/1
 
 
 
 
 
 
 
 
 
 
 
 
 
6/5**
W. Mc.
4/5
 
2/0
 
 
 
 
 
 
 
 
 
 
 
 
6/5 **
R. G.
 
3/4
0/2
 
 
 
 
 
 
 
 
 
 
 
 
3/6
 
 
 
 
 
 
 
Initial screening test
 
 
 
 
 
 
 
 
 
R. P.
3/10
 
 
0/1
0/1
 
 
0/3
 
0/3
0/5
 
 
 
 
3/23
A. R.
0/4
 
2/2
 
0/1
 
 
0/3
 
0/3
0/5
 
 
 
 
2/18
L. S.
5/10
2/4
2/5
 
 
 
 
0/3
0/3
0/3
0/5
0/5
 
0/3
 
9/41
M. B.
4/10
 
0/2
 
0/1
 
 
0/3
0/3
 
0/5
 
0/5
 
 
4/29
F. M.
1/2
 
 
 
 
 
1/1
 
 
 
 
 
 
 
 
2/3
W. M.
5/5
0/2
2/4
 
 
 
 
 
 
 
 
 
 
 
 
7/11
H. D.
0/3
 
4/12
 
 
 
 
0/3
0/3
0/5
 
 
 
 
 
4/26
H. C.
0/8
 
0/2
 
 
 
 
0/3
0/3
 
0/5
 
 
 
 
0/21
B. B.
4/10
1/1
2/2
 
 
 
1/1
0/3
3/3
0/3
 
 
 
 
 
8/23
A. F.
9/-
 
10/-
 
1/-
 
 
 
 
 
5/-
 
 
 
 
25/-
D. W.
0/2
2/3
 
 
 
 
 
3/3
0/3
 
 
 
 
0/3
 
5/14
F. V.
5/10
2/2
2/2
 
 
 
 
3/3
 
 
 
 
 
0/3
 
12/20
E. L.
0/6
 
2/2
 
 
 
 
0/3
 
 
 
 
 
 
 
2/11
C. H.
5/9
0/1
4/6
 
 
 
 
3/3
0/3
 
 
0/5
 
 
 
12/27
K. M.
1/3
1/0
0/2
 
 
 
0/1
 
0/3
 
 
 
 
 
 
2/9
J. F.
1/3
1/3
2/4
 
 
 
 
0/3
3/3
 
 
5/5
 
 
 
12/21
R. G.
6/10
1/0
2/0
 
 
 
 
0/3
3/3
 
0/5
0/5
0/5
0/3
0/10
12/44
 
 
 
 
 
 
 
 
Fourth week
 
 
 
 
 
 
 
 
R. P.
3/10
 
0/4
 
 
 
 
3/3
0/3
0/3
0/5
0/5
 
0/3
 
6/36
M. B.
1/10
 
 
 
 
 
 
0/3
0/3
0/3
 
 
0/5
 
 
1/24
F. M.
1/2
 
 
 
 
 
1/1
 
 
 
 
 
 
 
 
2/3
W. M.
9/9
2/0
2/6
 
 
 
 
 
 
0/3
0/5
 
 
 
 
13/23
H. D.
7/10
 
0/8
 
 
 
 
0/3
0/3
0/3
5/5
5/5
 
 
 
17/37
H. C.
 
 
4/4
 
 
 
0/1
3/3
0/3
 
 
 
 
 
 
4/11
B. B.
 
 
 
 
 
 
0/1
0/3
0/3
 
 
 
 
 
 
0/7
D. W.
5/3
2/2
 
 
 
 
1/1
3/3
0/3
 
0/5
 
 
 
 
11/16
F. V.
6/-
 
 
 
 
 
1/-
3/-
3/-
 
5/-
 
 
 
 
18/-
K. M.
 
1/2
2/4
 
 
 
 
 
3/3
 
 
 
 
 
 
6/9
J. F.
4/4
1/5
 
 
 
 
1/1
0/3
3/3
 
 
 
 
 
 
9/16
R. G.
10/-
 
2/-
 
 
 
1/-
3/-
3/-
 
5/-
 
 
 
 
24/-
 
 
 
 
 
 
 
 
Sixth week
 
 
 
 
 
 
 
 
R. P.
10/10
 
4/14
0/1
0/1
0/1
 
3/3
0/3
 
5/5
5/5
 
0/3
0/15
27/61
M. B.
6/10
 
0/10
 
 
 
 
3/3
3/3
 
0/5
 
 
0/3
 
12/34
F. M.
2/7
 
0/2
 
 
0/1
0/3
 
 
 
 
 
 
 
 
2/13
W. M.
0/2
 
0/2
 
0/1
0/1
 
 
 
3/3
0/5
 
 
 
 
3/14
H. D.
10/10
0/1
2/12
 
 
0/1
0/1
0/3
 
0/3
0/5
 
0/5
 
 
12/41
B. B.
0/8
 
0/2
 
 
 
1/1
3/3
3/3
 
 
 
 
 
 
7/17
D. W.
5/6
 
6/6
 
 
 
1/1
0/3
3/3
 
 
5/5
 
 
 
20/24
K. M.
4/
 
22/
 
 
 
 
 
3/-
 
5/-
 
 
 
 
34/-
J. F.
2/6
0/3
2/4
 
 
 
1/0
0/3
0/3
 
 
 
0/5
 
 
5/34
R. G.
7/-
 
 
 
 
 
1/-
3/-
3/-
 
5/-
 
5/-
 
 
24/-
 
 
 
 
 
 
 
 
Eighth week
 
 
 
 
 
 
 
 
M. B.
3/
 
 
 
 
 
 
3/
3/-
 
5/-
5/-
5/-
 
 
24/-
F. M.
1/10
 
 
 
0/1
 
1/1
0/3
 
 
 
 
 
 
 
2/15
W. M.
2/7
 
2/10
 
 
 
 
 
 
0/3
0/5
 
 
 
 
4/25
B. B.
9/10
1/1
2/2
 
 
 
1/1
3/3
0/3
 
 
 
 
 
 
16/20
J. F.
5/10
 
2/4
 
 
 
 
0/3
0/3
 
 
0/5
 
 
 
7/25
 
 
 
 
 
 
 
 
Tenth week
 
 
 
 
 
 
 
 
F. M.
8/10
 
 
 
 
 
1/1
3/3
0/3
 
 
 
0/5
 
 
12/22
W. M.
10/10
 
 
 
 
 
 
0/3
 
0/3
0/5
 
 
 
 
10/21
J. F.
10/10
1/0
4/0
 
 
 
 
0/3
0/3
0/3
0/5
0/5
 
 
 
15/29
 
 
 
 
 
 
 
 
Twelfth week
 
 
 
 
 
 
 
 
F. M.
4/10
1/1
 
 
 
 
1/1
3/3/
0/3
 
 
 
 
 
 
9/18

*In each instance the first figure is the appropriate score after 1mg, the second figure the score after 2 mg of malorphine . A zero or blank indicates no change or absence of that sign. A figure followed by a dash indicates that the 2 mg dose of nalorphine was not given in that test.

**Coded medication continued for less than two weeka, on account of patient's condition, transfer from hospital, or other cause, so that a second allyl test was not given.

TABLE 10 - Ally test point scores

Narcotic medication = Oxymorphone hydrochloride

 

Abstinence signs*

 

Patient

BP

T

R

Y

La

Rh

S

G

My

Tr

Re

C

D

Na

V

Total scores

 
 
 
 
 
 
 
 
Initial screening test
 
 
 
 
 
 
 
 
R. H..
2/8
 
4/4
 
 
 
 
 
 
 
 
 
 
 
 
6/9
M. C.
2/0
 
2/0
 
 
 
 
 
 
 
 
 
 
 
 
4/0 **
M. O
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0/0 **
S. M.
3/6
 
10/0
 
 
 
 
 
 
 
 
 
 
 
 
13/6 **
M. W.
10/10
 
16/22
 
 
1/1
1/1
3/3
0/3
0/3
5/5
0/3
 
 
 
36/51 ***
M. C.
0/4
3/4
6/6
 
 
 
 
 
 
 
0/5
 
 
 
 
9/19 ***
E. Z.
2/10
2/4
6/10
 
 
 
 
 
3/3
0/3
0/5
 
 
 
 
13/35***
A. Mc.
0/3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0/3
F. R.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0/0
S. R.
7/4
2/4
6/4
 
 
 
 
 
 
 
 
 
 
 
 
15/10
L. W.
1/2
2/2
 
 
 
 
 
 
 
 
 
 
 
 
 
3/4
E. A.
 
1/1
0/1
 
 
0/1
 
 
 
 
 
 
 
 
 
1/3 **
L. L.
 
4/1
 
 
 
 
0/3
 
 
 
 
 
 
 
 
4/4 **
A. S.
 
2/0
 
 
 
0/1
 
 
 
 
 
 
 
 
 
2/1
F. K.
0/2
6/7
4/2
 
 
 
 
 
 
 
 
 
 
 
 
10/11
H. Y.
2/1
 
 
 
 
 
0/3
 
 
 
 
 
 
 
 
2/4
L. G.
 
 
10/10
 
 
 
 
 
 
 
 
 
 
 
 
10/10
L. C.
7/2
1/1
 
 
 
 
 
 
 
 
 
 
 
 
 
8/3 **
D. R.
2/8
 
 
 
 
0/1
0/3
 
 
 
 
 
 
 
 
2/12 **
F. F.
0/2
10/9
 
 
 
1/0
 
 
 
 
 
 
 
 
 
11/11 **
L. H.
2/6
 
0/6
 
 
 
 
 
0/3
 
 
 
 
 
 
2/15 **
S. J.
5/6
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5/6
A. J.
0/3
0/3
 
 
 
 
 
 
 
 
 
 
 
 
 
0/6 **
F. O.
 
1/2
 
 
 
 
0/1
 
 
 
 
 
 
 
 
1/3
R. W.
0/1
0/1
 
 
 
 
 
 
 
 
 
 
 
 
 
0/2
R. P.
1/4
1/1
 
 
 
 
0/1
 
 
 
 
 
 
 
 
2/6
A. S.
1/1
 
4/6
 
 
 
 
 
 
 
 
 
 
 
 
5/7
 
 
 
 
 
 
 
 
Second week
 
 
 
 
 
 
 
 
R. H.
2/5
 
4/4
 
0/1
 
 
 
 
 
 
 
 
 
 
6/10
A. Mc.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0/0
F. R.
2/8
 
4/8
 
 
 
 
0/3
0/3
0/3
0/5
 
 
 
 
6/30
S. R.
4/9
0/2
 
 
 
1/1
 
 
3/3
 
 
 
 
 
 
8/15
L. W.
3/3
0/1
 
 
 
 
0/1
 
0/3
 
 
 
 
 
 
3/8
A. S.
1/4
1/1
2/0
 
 
 
 
 
 
 
 
 
 
 
 
4/5
F. K.
0/3
3/3
 
 
 
 
0/1
3/3
 
 
 
 
 
 
 
6/10
H. Y.
0/3
0/2
 
 
 
 
 
 
 
 
 
 
 
 
 
0/5
L. G.
10/10
 
2/2
 
 
 
 
 
 
 
 
 
 
 
 
12/12
S. J.
8/10
 
 
 
 
 
 
3/3
3/3
 
 
5/5
 
 
 
19/21
F. O.
2/3
2/2
10/6
 
 
 
0/1
 
 
 
0/5
 
0/5
 
 
14/22
R. W.
5/8
0/2
 
 
 
 
0/1
3/3
 
 
 
5/5
 
 
 
13/19
R. P.
4/10
0/2
 
 
 
 
 
 
 
 
 
 
 
 
 
4/12
A. S.
4/3
4/6
 
 
 
 
 
0/3
0/3
 
 
0/5
 
 
 
8/20
 
 
 
 
 
 
 
Fourth week
 
 
 
 
 
 
 
 
 
R. H.
1/2
0/2
 
 
 
 
0/3
0/3
 
 
 
 
 
 
 
1/10
A. Mc.
 
1/1
 
 
 
1/1
0/3
 
 
 
 
 
 
 
 
2/5
F. R.
0/3
 
0/4
 
 
 
 
 
 
 
 
 
 
 
 
0/7
S. R.
2/3
 
 
 
 
1/1
0/1
0/3
0/3
 
0/5
 
 
 
 
3/16
L. W.
 
4/5
2/4
 
 
 
1/1
0/3
0/3
 
0/5
 
 
 
 
7/21
A. S.
1/4
1/2
 
 
 
 
 
 
 
 
 
 
 
 
 
2/6
F. K.
10/10
2/2
 
 
 
 
1/1
3/3
0/3
 
0/5
 
 
3/3
 
19/27
H. Y.
1/10
 
 
 
 
 
 
0/3
 
 
 
 
 
 
 
1/13
L. G.
10/10
0/2
 
 
 
 
 
 
 
 
 
 
 
0/3
 
10/15
S. J.
7/-
 
4/-
 
 
 
 
3/-
 
 
5/-
 
 
3/-
 
22/-
R. P.
1/10
 
 
 
 
 
1/0
 
 
 
 
 
 
 
 
2/10
A. S.
1/5
1/1
2/4
 
 
 
 
0/3
3/3
 
 
5/5
 
 
 
12/16
 
 
 
 
 
 
 
 
Sixth week
 
 
 
 
 
 
 
 
R. H.
4/2
0/3
2/0
 
 
 
 
3/3
3/3
 
 
 
 
 
 
12/11
A. Mc.
2/9
 
 
 
 
 
 
3/3
 
 
 
 
 
 
 
5/12
F. R.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0/0
S. R.
4/-
6/-
8/-
 
 
1/-
1/-
3/-
3/-
3/-
5/-
 
 
3/-
 
37/-
F. K.
5/10
0/2
2/2
 
 
 
0/1
0/3
0/3
 
 
 
 
0/3
 
7/24
H. Y.
1/7
 
2/4
 
 
 
0/1
0/3
 
 
 
 
 
 
 
3/15
L. G.
10/10
0/1
2/2
 
 
 
 
 
0/3
 
 
 
 
 
 
12/16
 
 
 
 
 
 
 
Eighth week
 
 
 
 
 
 
 
 
 
A. Mc.
6/5
 
4/4
 
0/1
 
 
3/3
 
0/3
5/5
5/5
0/5
0/3
 
23/34
F. R.
2/0
 
2/6
 
 
 
 
 
 
 
0/5
 
 
 
 
4/11
F. K.
3/-
1/-
4/-
 
 
 
 
3/-
3/-
 
5/-
 
 
 
 
19/-
L. G.
8/10
0/2
0/1
 
0/1
 
 
 
3/3
 
0/5
0/5
0/5
0/3
 
11/35
 
 
 
 
 
 
 
 
Tenth week
 
 
 
 
 
 
 
 
A. Mc.
4/10
 
2/10
 
1/1
 
1/1
3/3
 
0/3
0/5
 
 
 
 
11/33
F. R.
1/7
3/5
8/8
 
 
 
 
 
 
3/3
0/5
 
 
 
 
15/28
F. K.
5/-
2/-
2/-
 
 
 
 
3/-
 
3/-
5/-
 
 
 
 
20/-
L. G.
10/-
 
2/-
 
 
 
 
 
3/-
 
5/-
5/-
 
3/-
 
28/-
 
 
 
 
 
 
 
Twelfth week
 
 
 
 
 
 
 
 
 
F.R.
2/2
2/1
6/8
 
 
 
 
 
0/3
0/3
0/5
 
 
 
 
10/22
L. G.
8/-
 
4/-
 
 
 
 
 
3/-
 
5/-
5/-
 
 
 
25/-

*In each instance the first figure is the appropriate score after 1mg, the second figure the score after 2 mg of malorphine . A zero or blank indicates no change or absence of that sign. A figure followed by a dash indicates that the 2 mg dose of nalorphine was not given in that test.

**Coded medication continued for less than two weeka, on account of patient's condition, transfer from hospital, or other cause, so that a second allyl test was not given.

TABLE 11 - Ally test point scores

Narcotic medication = Anileridine hydrochloride

 

Abstinence signs*

 

Patient

BP

T

R

Y

La

Rh

S

G

My

Tr

Re

C

D

Na

V

Total scores

 
 
 
 
 
 
 
 
Initial screening test
 
 
 
 
 
 
 
 
H. B
0/1
 
2/2
 
 
 
 
 
 
 
 
 
 
 
 
2/3
J. S.
8/2
2/0
4/4
 
 
 
 
 
 
 
 
 
 
 
 
14/6
J. H.
8/1
0/2
 
 
 
 
 
 
 
 
 
 
 
 
 
8/3
J. M.
I/10
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I/10
W. H.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0/0
I. R.
4/10
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4/10**
W. E.
2/5
 
4/6
 
 
 
0/1
0/3
0/3
 
 
 
 
 
 
6/18***
J. C.
3/8
 
2/0
 
 
 
 
 
 
 
 
 
 
 
 
5/8**
E. C.
0/6
 
 
 
 
 
 
3/3
 
 
 
 
 
 
 
0/6
N. B.
0/1
1/0
 
 
 
 
0/1
 
 
 
 
 
 
 
 
1/2
F. M.
 
1/1
 
 
 
 
 
 
 
 
 
 
 
 
 
1/1
R. Mc.
 
 
 
 
 
 
 
 
0/3
 
 
 
 
 
 
0/3
W. N.
 
 
4/2
 
 
 
0/1
 
 
 
 
 
 
 
 
4/3
M. D.
0/1
 
0/2
 
 
 
 
 
 
 
 
 
 
 
 
0/3**
E. C.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3/3**
J. T.
6/10
 
1/0
 
 
 
 
 
 
 
 
 
 
 
 
7/10**
J. S.
 
 
4/4
 
 
 
 
 
 
 
 
 
 
 
 
4/4**
P. P.
6/6
 
2/2
 
 
 
 
 
 
 
 
 
 
 
 
8/8
F. M.
4/2
2/2
 
 
 
 
 
 
 
 
 
 
 
 
 
6/4
F. L.
5/8
1/1
2/2
 
 
 
 
 
3/3
 
 
 
 
 
 
11/14
E. P.
?
 
2/2
 
 
 
 
 
 
 
 
 
 
 
 
3/4
J. C.
0/3
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0/3
J. M.
1/2
1/0
2/0
 
 
 
 
 
0/3
 
 
 
 
 
 
4/5**
M. F.
5/5
0/2
2/0
 
 
 
 
0/3
 
 
 
 
 
 
 
7/10
 
 
 
 
 
 
 
Second week
 
 
 
 
 
 
 
 
 
H. B
1/5
 
2/0
 
 
 
 
 
 
 
 
 
 
 
 
3/5
J. S.
0/1
 
 
 
 
 
 
0/3
0/3
 
 
 
 
 
 
0/7
J. H.
0/2
 
6/8
 
 
 
 
 
0/3
 
 
 
 
 
 
6/13
J. M.
2/10
3/4
0/2
 
 
 
 
0/3
0/3
 
 
 
 
 
 
5/22
W. H.
5/6
 
 
 
 
 
0/1
 
 
 
 
 
 
 
 
5/7
E. C.
4/5
 
 
 
1/0
 
 
 
 
3/0
 
 
 
 
 
8/5
N. B.
2/1
 
0/2
 
 
 
0/1
 
3/3
 
 
 
 
 
 
5/7
F. M.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
0/0
R. Mc.
2/4
 
0/2
 
 
 
 
0/3
 
 
 
 
 
 
 
2/9
W. N.
0/5
 
0/2
 
0/1
 
1/1
 
3/3
 
 
 
 
 
 
4/12
P. P.
1/3
1/4
0/2
 
 
 
 
3/3
 
 
 
 
 
 
 
4/12
F. M.
1/0
 
8/8
 
 
 
0/1
3/3
3/3
 
 
 
 
 
 
15/15
F. L.
3/7
0/2
2/8
 
 
 
 
3/3
3/3
 
0/5
 
 
 
 
11/28
E. P.
3/9
0/1
2/2
 
 
 
 
 
 
 
 
 
0/5
 
 
5/17
J. C.
5/8
 
2/6
 
 
 
1/0
 
 
 
0/5
 
 
 
 
8/19
M. F.
5/-
1/-
 
 
 
 
 
3/-
3/-
 
 
 
5/-
3/-
5/-
25/-
 
 
 
 
 
 
 
 
Fourth week
 
 
 
 
 
 
 
 
H. B
3/3
 
0/2
 
 
 
 
 
 
 
 
 
 
 
 
3/5
J. S.
1/5
 
4/10
 
 
 
0/1
0/3
 
 
0/5
 
 
 
 
5/4
J. H.
0/1
 
2/2
 
 
0/1
 
0/3
0/3
 
 
 
 
 
 
2/10
W. H.
0/3
 
0/8
 
 
0/1
 
0/3
0/3
 
 
 
 
 
 
0/18
N. B.
1/7
0/1
0/4
 
 
 
1/1
0/3
3/3
 
 
5/5
 
 
 
7/24
R. Mc.
4/9
 
2/4
 
 
 
 
 
 
 
 
 
 
 
 
9/16
W. N.
0/4
0/1
2/4
 
 
 
1/1
 
 
 
 
 
 
 
 
3/10
P. P.
6/10
 
2/5
 
 
 
 
0/3
0/3
 
0/5
0/5
 
 
 
8/31
F. M.
2/4
 
0/2
 
 
 
 
 
0/3
 
 
 
 
 
 
2/9
E. P.
4/7
 
2/4
 
 
 
 
3/3
3/3
 
 
 
 
0/3
 
12/20
M. F
10/-
 
 
 
 
1/-
 
3/-
3/-
 
 
 
 
3/-
 
20/-
 
 
 
 
 
 
 
Sixth week
 
 
 
 
 
 
 
 
 
H. B.
 
 
 
 
 
 
 
0/3
 
 
 
 
 
 
 
0/3
J. S.
6/9
 
11/9
 
 
0/1
0/1
3/3
0/3
0/3
5/5
 
 
0/3
 
25/37
R. Mc.
4/10
 
 
 
 
 
 
3/3
0/3
 
 
 
 
 
 
7/16
W. N.
4/4
0/1
4/6
 
 
 
 
3/3
3/3
 
 
 
 
 
 
14/17
F. M.
 
 
0/2
 
 
 
 
 
0/3
 
 
 
 
 
 
0/5
E. P.
5/7
 
 
 
 
 
1/1
0/3
0/3
 
 
5/5
 
3/3
0/25
14/47
 
 
 
 
 
 
 
Eighth week
 
 
 
 
 
 
 
 
 
H. B.
4/7
 
8/8
 
 
 
 
0/3
0/3
0/3
0/5
 
 
 
 
12/29
W. N.
1/9
 
 
 
 
 
 
3/3
3/3
 
0/5
 
 
 
 
7/20
F. M.
3/4
 
0/4
 
 
 
0/1
0/3
0/3
 
 
 
 
 
 
3/15
 
 
 
 
 
 
 
Tenth week
 
 
 
 
 
 
 
 
 
H. B.
10/10
 
4/8
 
1/1
 
1/1
3/3
 
3/3
5/5
 
 
 
 
27/31
 
 
 
 
 
 
 
Twelfth week
 
 
 
 
 
 
 
 
 
H. B.
5/5
 
4/6
 
1/1
 
 
3/3
3/3
3/3
5/5
 
 
 
 
24/26

*In each instance the first figure is the appropriate score after 1mg, the second figure the score after 2 mg of malorphine . A zero or blank indicates no change or absence of that sign. A figure followed by a dash indicates that the 2 mg dose of nalorphine was not given in that test.

**Coded medication continued for less than two weeka, on account of patient's condition, transfer from hospital, or other cause, so that a second allyl test was not given.

TABLE 12 - Summary of allyl test scores*

 

Point scores** (weeks)

 

Patient

Initial

2

4

6

8

10

12

First score indicative of developing physical dependence (week)

 
 
 
 
Morphine medication
 
 
 
 
A. R.
12/6
2/18
 
 
 
 
 
Second
L. S.
0/0
9/41
         
Second
R. P.
0/0
3/23
6/36
27/61
     
Second
M. B.
0/0
4/29
1/24
12/34
24/ -
   
Second
F. M.
3/6
2/3
2/3
2/13
2/15
12/22
9/18
Eighth
W. M.
3/5
7/11
13/23
3/14
4/25
10/21
 
Fourth
H. D.
2/11
4/26
17/37
12/41
     
Second
H. C.
6/3
0/21
4/11
       
Second
B. B.
7/9
8/23
0/7
7/17
16/20
   
Second
A. F.
4/201
25/ -
         
Second
D. W.
2/3
5/14
11/16
20/24
     
Fourth
F. V.
10/19
12/20
18/ -
        2
E. L.
4/6
2/11
          3
C. H.
5/7
12/27
         
Second
K. M.
1/1
2/9
6/9
34/ -
     
Sixth
J. F.
3/9
12/18
9/16
5/24
7/25
15/29
 
Second
R. G.
3/6
12/44
24/ -
24/ -
     
Second
Average
4/6.5
7/21
9/16+
13/24+
11/21+
12/23+
 
About third
       
Oxymorphone medication
       
R. H.
6/9
6/10
1/10
12/11
      4
A. Mc.
0/3
0/0
2/5
5/12
23/34
11/33
 
Eighth
F. R.
0/0
6/30
0/7
0/0
4/11
15/28
10/22
Tenth5
S. R.
15/10
8/15
3/16
37/ -
     
Second
L. W.
3/4
3/8
7/21
       
Fourth
A. S.
2/1
4/5
2/6
        3
F. K.
10/11
6/10
19/27
7/24
19/ -
20/ -
 
Fourth
H. Y.
2/4
0/5
1/13
3/15
     
Sixth
L. G.
10/10
12/12
10/15
12/16
11/35
28/ -
25/ -
Fourth
S. J.
5/6
19/21
22/ -
       
Second
F. O.
1/3
14/22
         
Second
R. W.
0/2
13/19
         
Second
R. P.
2/6
4/12
2/10
        3
A. S.
5/7
8/20
12/16
       
Second
Average.
4/5.5
7/14
6.7/13+
11/13+
14/27+
18.5/30+
 
About fourth
       
Anileridine medication
       
H. B.
2/3
3/5
3/5
0/3
12/29
27/31
24/26
Eighth
J. S.
14/6
0/7
5/24
25/37
     
Fourth
J. H.
8/3
6/13
2/10
        4
J. M.
1/10
5/22
         
Second
W. H.
0/0
5/7
0/18
       
Fourth
E. C.
0/6
8/5
          3
N. B.
?
5/7
7/24
       
Fourth
F. M.
1/1
0/0
          3
R. Mc.
0/3
2/9
9/16
7/16
     
Fourth
W. N.
4/3
4/12
3/10
14/17
7/20
   
Sixth
P. P.
8/8
4/12
8/31
       
Fourth
F. M.
6/4
15/15
2/9
0/5
3/15
   
Second6
F. L.
11/14
11/28
         
Second
E. P.
3/4
5/17
12/20
14/47
     
Second
J. C.
0/3
8/19
         
Second
M. F.
7/10
25/ -
20/ -
       
Second
Average.
4/5
7/13+
6.5/16.7
 
10/21
   
About fourth

*Includes only patients who received at least two allyl tests

**First figure total score after 2 mg, second figure total score after 2 mg of nalorphine. Where there is a dash instead of second figure, 2mg dose was not given

1Initial high score due to blood pressure and respiratory rate changes.

2Some physical depence present initially; it increased rapidly in intensity. This patient is not included in discussion of physical depence development.

3Definite physical depence not apparent during short period of drug administration.

4Score in fourth week below arbitrarily chosen level of significance but includes values for goose flesh and mydriasis after both doses of nalorphine. Some physical dependence probable.

5 No apparent explanation for high score with some characteristic signs in second week, and low scores in later weeks.

6Earlier period score taken as significant because of appearance of mydriasis with each allyl test.

TABLE 13 - Summary of placebo tests

   

Signs looked for*

 

Test

Number of patients

BP

T

R

Y

La

Rh

S

G

My

Tr

Re

Average scores per patient

First .
56
37/136
27/76
24/66
 
 
 
4/4
6/18
 
 
 
5/4
Second
36
22/80
15/37
18/60
 
1/1
 
 
2/6
 
 
 
5.0
Third
23
13/54
7/17
12/44
 
 
 
1/1
3/9
 
 
 
5.4
Fourth .
10
7/25
5/11
8/24
 
 
 
 
1/3
 
 
 
6.3
Fifth .
9
2/3
4/11
4/14
 
 
 
1/1
2/6
 
 
 
4.0
Sixth
4
2/2
1/2
3/6
 
 
 
 
 
 
 
1/5
4.0
TOTAL
138
 
 
 
 
 
 
 
 
 
 
 
5.2 (Aver.)
Individual scores
 
 
 
 
 
 
 
 
 
 
 
 
Total
Patient H. B.
 
2 2 8
 
 
 
 
 
 
 
 
12
,, L. G. .
 
10 4 2
 
 
 
 
 
 
 
 
16
,, W. N.
 
10 12 4
 
 
 
 
 
 
 
 
261
,, L. W.
 
7 4 4
 
 
 
 
 
 
 
 
15
,, J. S.
 
1 4 8
 
 
 
 
 
 
 
 
13
,, R. Mc. .
 
3 5
 
 
 
 
 
3
 
 
 
112
,, ,,
 
7 4 4
 
 
 
 
3
 
 
 
182
,, ,,
 
5 4 4
 
 
 
 
3
 
 
 
162

** First figure indicates number of patients in whom change or sign was observed; the second figure is the total score for that sign for all patients. A blank indicates that the sign was not observed. Gastrointestinal signs have been omitted from this tabulation because they were never seen in placebo tests.

1Sharp rise in temperature due to intercurrent infection.

2Three placebo tests on same patient, in each of which goose flesh was noted. See table 12 for his scores on ally1 tests.

There were three patients on morphine (W. M., H. C. And B. B.), one patient on oxymorphone (F. R.) and one on anileridine (F. M.) who showed a significantly high score on the allyl test after two weeks and a lower score after four weeks of drug administration. For all these patients except F. R., the difference was almost entirely due to diminution in blood pressure and respiratory rate changes, signs such as sweating, goose flesh and mydriasis appearing at each test. In the case of F. R., goose flesh, mydriasis, tremor and restlessness were reported for the allyl test at two weeks and none of these signs was seen in the four- or six-week test. Restlessness reappeared at the eighth week, tremor and restlessness at the tenth week, and mydriasis, tremor and restlessness at the twelfth week test. No explanation has been found for this discrepancy.

The second or later allyl test in the same individual sometimes produced discomfort in addition to the signs noted in the tables (tables 9, 10 and 11) and indicative of physical dependence. This has been summarized in table 14. Practically all these symptoms or complaints are a part of Isbell's description of the nalorphine precipitated abstinence syndrome (Isbell, 1953) and while not included in the Himmelsbach scoring system or readily amenable to numerical evaluation, they would seem to be further evidence of developing physical dependence.

Occasionally (also indicated in table 14) the administration of nalorphine appeared to cause the recurrence of pain, and restoration of comfort to the patient by injection of his coded drug might then be temporarily difficult. However, the allyl test is practicable and can be used as a physical dependence yardstick in clinical practice. There must be careful observation, and generally, to avoid undue patient discomfort, the 2 mg nalorphine dose should be omitted when the score after the 1 mg dose becomes significant.

SUMMARY Morphine sulfate, oxymorphone hydrochloride and anileridine hydrochloride were administered under code numbers on a double blind basis to cancer patients with chronic pain in an amount and at an interval just sufficient for control of pain. The period of administration varied from two to twelve weeks. The initial doses were based on previously determined analgesic dose equivalence of the three drugs (morphine sulfate 10 mg, oxymorphone hydrochloride 1.0 mg, and anileridine hydrochloride 25 mg per 60 kg body weight).

Weekly pain relief scores were recorded as a check on adequacy of pain relief, and a careful record was kept of narcotic administration, both individual dose and daily amount, as a check on the development of tolerance. Most, but not all, patients developed tolerance to each drug during the period of observation, probably to a greater extent with oxymorphone and anileridine than with morphine.

Before beginning coded medication and at two-week intervals during such medication, each patient received one mg followed in twenty-five minutes by two mg of nalorphine to detect the existence of physical dependence by precipitation of characteristic abstinence signs. This was checked by the administration of a placebo under the same conditions in alternate weeks.

TABLE 14 - Unusual discomfort or recurrence of pain during allyl test

Patient

Narcotic Medication

Recurrence of pain during test

Unusual discomfort

Anxiety, apprehension, etc

Week of allyl test

Remarks

Amc
C
Noted
 
Irritability
Eighth
Complains of noise and need to be disturbed, latter part of test
J S
D
 
Crawling sensation all over
 
Second
 
"
 
 
 
Anxiety
Sixth
 
R P
E
Noted
 
Apprehension
Sixth
Feelings of chilliness and numbness
"
 
 
 
 
Sixth
Hot and cold sensations
L S
E
Noted
 
 
Second
Feeling hot all over
F R
F
Noted
 
Apprehension
Tenth
 
M B
G
Noted
 
,,
Second
Feeling of chilliness
"
 
 
 
,,
Eighth
 
FM
J
Noted
 
 
Second
Feeling of warmth
"
 
 
Crawling sensation all through body
 
Tenth
Dizziness
L W
N
 
 
 
Fourth
Hot and cold sensations
H D
O
 
Felt bad all over
Irritability
Second
Feelings of chilliness
F K
A
 
Vague discomfort
 
Fourth
Unable to explain
"
 
Noted
 
 
Sixth
Feels hot all over
"
 
Noted
Very uncomfortable
Bad mood
Eighth
 
R Mc
B
Noted
 
 
Sixth
Discomfort of sudden onset 10 min after 2 mg dose of nalorphine
N B
B
Noted
 
 
Second
 
"
 
Noted
 
 
Fourth
 
H. Y..
C
 
Marked feeling of discomfort
 
Fourth
Unable to explain. Feels tipsy
L. G. .
C
Noted
 
 
Eighth
Intense, patient in tears
".
 
Noted
 
 
Tenth
 
".
 
Noted
 
 
Twelfth
Emotionally disturbed
W. N. .
D
Noted
 
 
Eighth
 
P. P. .
D
 
Marked dysphoria
Surly
Fourth
Unable to explain
B. B.
E
 
Crawling sensation
 
Second
 
"
 
 
Crawling sensation
 
Fourth
Feeling of warmth inside
".
 
 
 
 
Sixth
Feeling of drunkenness. This patient claims sensations pleasant
H. C.
C
 
Uncomfortable
 
Second
Unable to explain
".
 
 
Uncomfortable
 
Fourth
" "
S. J. .
F
 
Uncomfortable all over, not pain
 
Second
Unable to explain
"
 
Noted
Felt bad all over
Apprehension
Fourth
Emotionally disturbed
D. W..
G
 
Felt queer, not pain
 
Second
Unable to explain
 
 
Noted
Crawling sensation, feels "terrible"
 
Fourth
Unable to explain
"
 
 
Felt "funny" all over
 
Sixth
Burning through whole body
F. V. .
G
Noted
 
 
Second
 
".
 
Noted
Felt "funny" all over
 
Fourth
Feeling of warmth
F. M.
H
 
 
Severe dysphoria
Eighth
Feeling of warmth
K. M.
J
 
Vague discomfort
 
Fourth
Feeling of warmth
"
 
Noted
 
Apprehension
Sixth
 
E. P.
K
Noted
General discomfort
 
Fourth
Feeling of warmth. The test "upsets" her
"
 
Noted
" "
 
Sixth
 
F. L.
K
 
General discomfort
 
Second
 
J. F.
L
 
Something wrong
 
Second
Unable to explain. Feeling of chilliness
".
 
 
Crawling sensation, general discomfort
 
Fourth
Hot and cold sensations
"
 
 
Felt queer
 
Sixth
Hot and cold sensations
".
 
 
General discomfort
 
Tenth
Chilliness
R. W.
M
Noted
 
 
Second
Chilliness, feeling of swelling up
R. P.
M
Noted
 
 
Second
 
"
 
Noted
 
 
Fourth
 
A. S.
N
 
 
Surly
Fourth
Headache
R. G.
O
Noted
 
Upset
Second
 
"
 
Noted
 
 
Fourth
 
"
 
Noted
 
 
Sixth
 
J. C.
P
 
Vague discomfort
Irritability
Second
Feeling of warmth. Dizziness
M. F.
P
 
Choking sensation
 
Fourth
Feeling of chilliness

Narcotic medication : F, G, J, L, O = Morphine sulfate; A, C, F, M, N = Oxymorphone hydrochloride; B, D, H, K, P = Anileridine hydrochloride.

Physical dependence was detectable by the allyl test (nalorphine administration) usually in two to four weeks with morphine and in about four weeks with oxymorphone or anileridine.

While nalorphine during chronic narcotic administration may cause some discomfort and may occasionally cause the recurrence of pain, it can be used successfully to indicate the development of physical dependence on the narcotic.

The intensity of the abstinence syndrome precipitated by nalorphine is not necessarily indicative of the intensity of abstinence signs to be expected following abrupt termination of narcotic administration.

References

EDDY, N.B. HALBACH, H. & BRAENDEN, O.J. (1956) Bull. Wld Hlth Org. 14. 353.

EDDY, N.B., HALBACH, H. & BRAENDEN, O.J. (1957) Bull. Wld Hlth Org. 17, 569.

EDDY, N. B. & HIMMELSBACH, C. K. (1936) Publ. Hlth Rep. (Wash). Suppl. No. 118.

HIMMELSBACH. C. K. (1939) J. Pharmacol. 67, 239.

ISBELL, H. (1953) The Merck Report, April.

ISBELL, H. et al. (1948) Arch. Int. Med. 82, 362.

LASAGNA, L. & BEECHER, H. K. (1954) J. Amer. Med. Ass. 156, 230.

LEE, L. E. Jr. (1942) J. Pharmacol. 75, 161.

WALLENSTEIN, S. L. & HOUDE, R. W. (1956) Fed. Pro. 15, 495.

WIKLER, A., Fraser, H. F. & ISBELL, H. (1953) J. Pharmacol. 109, 8.