Effect of a cycle of addiction to intravenous heroin on certain physiological measurements

Sections

Introduction
Methods
Results
Discussion
Summary

Details

Author: H. F. FRASER,, B. E. JONES,, D. E. ROSENBERG, , A. K. THOMPSON
Pages: 17 to 23
Creation Date: 1964/01/01

Effect of a cycle of addiction to intravenous heroin on certain physiological measurements

H. F. FRASER,
B. E. JONES,
D. E. ROSENBERG,
A. K. THOMPSON
from the National Institute of Mental Health, Addiction Research Center, PHS Hospital, Lexington, Ky., U.S.A.

Introduction

Although 94 per cent of opiate addicts in the United States abuse heroin by the intravenous route [ 1] , only two controlled studies have been reported on the effects of intravenous heroin chronically administered according to an addictive schedule [ 2] , [ 3] . The purpose of this paper is to amplify our knowledge respecting the effects of a cycle of addiction to intravenous heroin on selected physiological measurements.

Methods

1. Experimental Setting. Fraser et al. [ 3] have studied the effects of addiction to intravenous heroin on physical activity in man. In that report details of the physical features of the research wards, regulations, operations conducted thereon, recreational activities available to experimental patients, and the work assignments of such patients were described and apply to this investigation.

2. Subjects. The 5 subjects who volunteered for this experiment were white or Negro males who were incarcerated for violation of federal narcotic laws. All had long histories of addiction to opiates, had relapsed to narcotics repeatedly, were over 25 years of age, and physically healthly. Although all were classified as having character disorders, none showed major psychiatric deviations. Although at the time this study began each patient had been withdrawn from opiates for several months, some had received various types of drugs intermittently in single doses at weekly intervals in more recent tests.

In addition to the data obtained from 5 subjects described above, certain results from 5 other subjects who had participated in an identical addiction regimen with heroin [ 3] , not previously described, will be reported.

3. Experimental Plan and Schedule of' Medication. Patients and observers were familiarized with the experimental procedures by participating without medication for seven days. Thereafter, in a double-blind fashion, each subject received four intravenous injections daily of medication as subsequently described. The first phase lasted 28 days, during which time every injection was a placebo, except on the 17th day when a single intravenous injection of 8 mg of heroin hydrochloride was given at 9:30 a.m. During the next phase, which lasted 61 days, subjects were addicted to intravenously administered heroin. The initial total daily dosage of heroin hydrochloride averaged 10 mg, administered intravenously in four equally divided doses; thereafter the total daily dosage was gradually increased with an average of 96 mg attained by the 18th day and maintained at that level for 42 more days (figure 1). The plan was to attain a maximum daily dose of approximately 1.2 mg/kg. On the 62nd day of the addiction cycle the patients received only their 6 a.m. medication; on the 63rd and 64th days only minimal doses of heroin; on the 65th day each patient received two doses of heroin at the stabilization level which was thereafter gradually and correspondingly reduced during the succeeding six days (figure 2).

4. Clinical Observations. Rectal temperature, pulse rate, blood pressure and respiratory rate were recorded three times daily. Patients rested in bed for at least 10 minutes prior to these observations. Weight and caloric intake were also recorded daily. Complete blood counts, urinalysis and two liver function tests were made every two weeks. Intensity of abstinence (withdrawal signs) during reduction and withdrawal of heroin was evaluated daily according to the procedure of Kolb & Himmelsbach [ 4] .

FIGURE 1. - The upper line illustrates the frequency of eyes closed (" nodding ") for each individual subject at intervals throughout the placebo and heroin addiction periods. Each point is an average of 6 daily observations. As explained in the text, each subject was observed for closed eyes at two-minute intervals for one hour daily while the subjects were watching a television programme. The lower portion of figure I illustrates the daily dose of heroin (average for the 5 subjects) throughout the experimental period.

Full size image: 48 kB, FIGURE 1

5. Measurements of Physical Activity

  1. Hours lying horizontal on bed in room. This was recorded twenty-four hours a day at half-hour intervals by trained observers, and was scored as positive irrespective of whether the patient was sleeping, resting, reading, etc. [ 3] .

  2. Hours of sleep. This was recorded at half-hour intervals daily and was scored positive only when the patient was lying in bed sleeping, as indicated by failure to respond when an aide entered his room [ 3] .

  3. Hours off the research ward. This was recorded at half-hour intervals daily and was checked positive regardless of whether the patient left the ward on his own option or to perform a work assignment [ 3] .

6. Observation for Degree of " Nodding " (eyes closed). During intoxication with opiate-type drugs patients are mildly sedated, a conspicuous feature of which is " nodding ". When " nodding ", a patient closes his eyes and often his head drops to his chest. This may occur while patients are sitting quietly, while engaged in conversation, or while watching a television programme. They are, however, readily arousable from this apparent somnolent condition. The incidence of nodding was measured as follows: Patients were observed in a "dayroom " during a one-hour period (8-9 p.m., Monday through Friday) during which time programmes which normally interested the experimental subjects were presented on television. Observations began 4 ? hours after an injection of heroin and were made through a one-way window from an adjacent room. At two-minute intervals, signaled by a timing device, the observer rapidly inspected each subject to ascertain whether his eyes were closed. The timing device was muted so it was not heard by the subjects. Interim observations were not made within the two-minute intervals. Subjects were permitted to leave the room only for bathroom privileges. Each two-minute interval of absence from the room was recorded by a zero symbol, but since such absences were rare and of short duration, they were not considered in computing the data.

7. Coding Test Performance. During the pre-addiction and addiction periods the patient's performance on a coding test was measured. The test was a paper-and-pencil task consisting of a page of random numbers with instructions to mark out two assigned numbers. One of the assigned numbers was to be marked out only when it immediately preceded an odd number, while the other assigned number was to be marked out only when it immediately preceded an even number.

FIGURE 2. - A comparison of the mean intensity of abstinence for 5 subjects on the 61st day of chronic heroin administration with that observed when the dosage of heroin was [ 1] acutely reduced, [ 2] gradually withdrawn and [ 3] completely withdrawn.

Full size image: 54 kB, FIGURE 2

Eight different sheets of random numbers were used in conjunction with five different pairs of assigned numbers, so that for each weekly test session a different combination of assigned numbers and page of random numbers was available. The task demanded persistent close attention, and required an average time of about 12 minutes to complete.

The test was always administered one hour after intravenous medication. Four of the first five weekly tests were administered during the pre-addiction period when the patients received saline placebos, but the fifth test was given in the fourth week after they had received a single 8-mg dose of heroin intravenously.

Results

1. Clinical Observations: Comparison of Effects of Placebo and Heroin. The effects on rectal temperature, respiratory rate and systolic blood pressure for the 5 subjects involved in this experiment (R.S., J.N., M.E., M.Y. and M.S.H.), together with those of 5 subjects previously studied on a comparable regimen (3), are summarized in table 1. Chronic administration of heroin increased the average rectal temperature for 8 of the 10 subjects, one showed no change, and the other only a very slight reduction of temperature (0.1 °C). The increase was statistically significant for the group (paired t-test), and individually in 6 of 8 subjects (standard t-test). Respiratory rate was significantly depressed in 8 of the 10 subjects, one was slightly but not significantly depressed, and in the last subject the rate was slightly but significantly increased (table 1). Systolic blood pressure was not altered when the observations of the 10 subjects were averaged (table 1). However, several individual subjects had significant decreases or increases in blood pressure during heroin intoxication as compared to placebo. All subjects gained weight on placebo, whereas at the end of addiction they had all lost weight (2.80-8.93 kg, table 2). Vomiting was not observed in any subject on placebo, whereas it was frequently observed during addiction to heroin. Furthermore, complete tolerance to the emetic effect of heroin was not acquired (table 2). During heroin administration all subjects showed a moderate decrease in caloric intake. As compared to placebo, no significant changes were observed in complete blood counts, urinalysis or liver function tests. Except for the episodes of vomiting, mild anorexia, and weight loss, their general health remained good throughout the experimental period.

TABLE 1

A comparison of the mean daily rectal temperature, respiratory rate and systolic blood pressure during the chronic intravenous administration of a placebo (28 days) and heroin (61 days)

 

Rectal temperature

 

Respiratory rate

 

Systolic blood pressure

 

Subject

Placebo

Heroin

Difference

Placebo

Heroin

Difference

Placebo

Heroin

Difference

R.S.
36.86 37.08
+ 0.22 ***
16.37 12.13
- 4.24 ***
110.18 103.16
- 7.02 ***
J.N.
36.72 36.99
+ 0.27 ***
13.11 13.02
- 0.09
97.30 99.28
+ 1.98 *
M.E.
37.11 37.10
- 0.01
14.00 10.77
- 3.23 ***
116.70 112.20
- 4.50 **
M.Y.
37.01 37.24
+ 0.23 ***
19.89 20.88
+ 0.99 **
118.67 119.64
+ 0.97 *
S.H.
37.04 37.12
+ 0.08 *
21.81 16.13
- 5.67 ***
115.44 112.38
- 3.06 **
C.R.
36.85 39.96
+ 0.11 *
16.14 13.57
- 2.57 ***
109.29 113.87
+ 4.58 ***
C.A.
37.08 37.19
+ 0.11
16.57 13.62
- 2.95 ***
116.75 117.80
+ 1.05
G.L.
36.88 36.88 0.00 14.86 12.92
- 1.94 ***
111.18 109.57
- 1.61 *
J.O.
36.61 36.69
+ 0.08
20.36 19.08
- 1.28 **
113.50 123.35
+ 9.80 ***
M.A
36.95 37.12
+ 0.17 **
16.46 12.52
- 3.94 ***
103.75 107.70
+ 3.95 ***
Mean
36.91 37.04
+ 0.13 **
19.96 14.46
- 2.49 **
111.28 111.90
+ 0.61

P<0.05 ** P<0.01 *** P<0.001

Each individual difference represents the daily mean for the placebo period as compared to that obtained during chronic heroin administration for each individual subject. Significance of each individual difference was evaluated by the standard t-test; and significance for the group by the paired t-test.

2. Comparison of Placebo with Heroin respecting Hours Horizontal in Bed Daily, Hours of Sleep Daily and Hours

TABLE 2

A comparison of the mean daily rectal temperature, respiratory rate and systolic blood pressure during the chronic intravenous administration of a placebo (28 days) and heroin (61 days)

 

Body weight* Gain or loss (kg)

Vomiting **

Day of addiction vomiting first and last occurred

Subject

Placebo

Heroin

Placebo

Heroin

First

Last

R.S.
+ 1.21
- 3.79
0 15 10 54
J.N.
+ 0.62
- 2.80
0 29 2 55
M.E.
+ 0.85
- 3.39
0 19 10 44
S.H.
+ 3.43
- 8.93
0 16 12 43
M.Y.
+ 1.38
- 4.40
0 20 6 52
Mean.
+ 1.50
- 4.66
0 20 6 50

Each value represents the difference in weight on the last day of an experimental period as compared with the first day.

Each value for vomiting represents the total number of episodes during the experimental periods.

Off the Ward Daily. This is enumerated for the 5 subjects in this test in table 3. Over-all the effects of heroin were to depress activity in 4 of the 5 subjects, but in one subject the average effects of heroin were to increase physical activity, although not significantly. Hours lying horizontal in bed daily proved to be a sensitive index of reduced activity. Differences for the above parameters were not significant by the paired t-test.

3. Observation for " Nodding " (eyes closed). Figure 1 shows the extent to which each patient " nodded " while receiving intravenous placebo and heroin chronically. Three of these subjects (R.N., M.Y. and S.H.) showed a significant increase in " nodding " (P < .01) during heroin intoxication. In one subject the increase in " nodding " was moderate and not significant. Subject M.E. showed slightly less " nodding " on heroin as compared to placebo. The extent to which patients exhibited " nodding " during the observation periods increased as the dosage was advanced to maximum; the average peak effect was observed usually after one month of heroin, subsiding somewhat thereafter (figure 1).

4. Coding Test Performance. The subjects showed improvement in both time and error scores on the first three tests administered during the placebo period, while the scores on the last two placebo tests were relatively stable. Compared with these last two placebo tests neither the single 8 mg dose nor the opiate addiction period produced any significant impairment of performance (figure 3).

During the placebo period and the first six weeks of the addiction period each subject worked until he had completed the test. On the seventh week of the addiction period the subjects were stopped, without prior warning, after they had worked for six minutes on the test. The following week, the eighth week of the addiction period, the subjects were told before beginning the test that it would be timed, and that they would have the same amount of time to work as the week before. The timing of the tests was introduced to determine if the subjects would be responsive to what was considered a slight increase in incentive toward improved performance. On the second timed test, when the subjects knew they would be timed, each subject completed more work than he had in the same amount of time the previous week. The mean for the group changed from 29 lines of work completed to 37 lines, an increase of over 27 %. This change was significant at less than the .05 level of probability. There was a slight but nonsignificant reduction in the mean number of total errors and the mean number of errors per line of work completed.

TABLE 3

A comparison of the mean daily hours of sleep, hours lying horizontal in bed and hours off the ward during the chronic intravenous administration of a placebo (28 days) and heroin 61 (days)

 

Hours horizontal in bed daily

 

Hours sleep daily

 

Hours off ward daily

 

Subject

Placebo

Heroin

Difference

Placebo

Heroin

Difference

Placebo

Heroin

Difference

R.S.
10.89 10.07
- 0.82
6.71 6.15
- 0.56
1.32 1.69
+ 0.37
J.N.
9.66 10.78
+ 1.12 *
6.29 6.92
+ 0.63
3.63 2.80
- 0.83*
M.E.
10.50 13.86
+ 3.81 ***
7.03 8.49
+ 1.46**
0.18 0.56
+ 0.38**
M.Y.
8.95 10.28
+ 1..33 **
5.89 7.15
+ 1..26*
3.79 2.09
- 1.70*
S.H.
9.39 11.01
+ 1.62 ***
6.53 6.75
+ 0.22
3.68 2.50
- 1.18***
Mean
9.78 11.20
+ 1.42
6.49 7.09
+ 0.60
2.52 1.93
- 0.59

P<0.05 ** P<0.01 *** P<0.001

Each difference represents the daily mean for the placebo period as compared to that obtained during chronic heroin administration for each individual subject. Significance for individual differences was evaluated by the standard t-test; and significance for the group by the paired t-test.

These results suggest that in former opiate addicts small single doses of heroin and periods of addiction extending to 60 days do not necessarily impair performance on a mental task which requires close attention and brief but persistent work. The results of the timed test during addiction indicate that the subjects were responsive to a mild incentive.

FIGURE 3. - The line joining the open circles shows the mean time required by the experimental subject to complete the coding tests, while the line joining the open triangles illustrates the mean number of errors of 5 subjects under placebo conditions and while addicted to heroin.

Full size image: 18 kB, FIGURE 3

5. Intensity of Abstinence during Reduction of Heroin and Withdrawal. A sharp reduction of dosage of heroin was followed by quite severe signs of abstinence which promptly declined after heroin was again administered, and when heroin was completely discontinued after six days of gradual reduction a slight increase in intensity of abstinence again was observed which persisted to a mild degree during the next ten days (figure 2). The abstinence syndrome observed following chronic administration of intravenous heroin resembled that described when morphine was abruptly withdrawn after being chronically administered intravenously [ 2] and subcutaneously [ 4] .

Discussion

In an analogous study, Fraser et al. [ 3] compared the effects of intravenously administered placebo and heroin. As compared to placebo, they observed that heroin initially increased activity for three or four days but subsequently depressed activity when chronically administered. Furthermore, during chronic heroin administration the patients showed a pronounced tendency to retreat from all forms of activity and social contacts, to go to their rooms to lie on their beds, eyes closed, frequently with radios turned on, and " nodding." Even though these patients showed depressed physical activity while chronically intoxicated on heroin, their performance on a pursuit rotor test was not impaired. Since the above patients remained in relatively good physical health, and performed satisfactorily in a pursuit rotor test during addiction to heroin, it was concluded that the depressed physical activity was not due to debility or psychomotor impairment but rather suggested a reduced responsiveness to ambient stimuli while chronically receiving heroin [ 3] . The observations and conclusions of the previous experiments [ 3] respecting physical activity and degree of contact with environment as influenced by chronic intoxication with heroin are confirmed and extended by the present study.

Although the respiratory rate was significantly depressed by heroin, the effect on systolic blood pressure appeared to vary between individual subjects; for example, of the 10 subjects 4 showed a significant increase, while 4 others showed a significant decrease, so that the average effect was nil.

The slight but significant increase in average daily rectal temperature for some subjects and repeated episodes of vomiting and loss of weight during the chronic administration of heroin suggests difficulty in acquiring tolerance to these effects.

Summary

Selected physiological measurements were determined on 5 former heroin addicts while receiving an intravenous placebo for 28 days. These subjects were then addicted for 61 days to intravenous heroin HCl and the observations repeated. The average initial daily dose of heroin was 10 mg; this was increased to an average of 96 mg on the 18th day of addiction and maintained at that level for 43 additional days. The experimental design was double-blind (a parallel experiment was carried out on 5 other subjects and certain measurements in this study, not previously reported, are included herein).

In 4 of the 5 subjects, heroin as compared with a placebo depressed physical activity as indicated by increased hours of sleep, increased hours lying horizontal in bed, and reduced hours off the research ward daily. Heroin provoked repeated episodes of vomiting and a loss of weight in all subjects. The incidence of " nodding " (observations for closed eyelids while subjects were viewing a television programme) was increased in 4 of the 5 subjects while receiving heroin. Over-all the health of the subjects was satisfactory throughout this experimental period. Performance of a coding test which required close attention for an average of 12 minutes showed no impairment during addiction. During addiction the subjects showed an improvement in performance upon introduction of a mild incentive (timing the test).

After 61 days of chronic intoxication with heroin a sharp reduction of the dosage of heroin was followed by quite severe signs of abstinence which promptly declined after heroin was again administered. The abstinence syndrome resembled that observed after withdrawal of morphine.

In 8 of 10 subjects (utilizing data from both experiments) heroin as compared to a placebo significantly depressed respiratory rate, and in 8 of the 10 subjects, rectal temperature was significantly increased. The effect on systolic blood pressure varied among the 10 subjects but the average effect was nil.

References

001

U.S. Federal Bureau of Narcotics, Statistical data of active narcotic addicts in the United States as of September 30, 1961.

002

Martin, W. R. & Fraser, H. F.: A comparative study of physiological and subjective effects of heroin and morphine administered intravenously in post-addicts. J. Pharmacol. & Exper. Therap ., 133: 388-399, 1961.

003

Fraser, H. F., Jones, B. E., Rosenberg, D. E. & Thompson,

A. K.: Effects of addiction to intravenous heroin on patterns of physical activity in man. Clin. Pharmacol. & Therap ., 4: 188-196, 1963.

004

Kolb, L. & Himmelsbach, C. K.: Clinical studies of drug addiction. III. A critical review of the withdrawal treatments with method of evaluating abstinence syndromes. Am. J. Psychiat ., 94: 759-797, 1938.