General methodology
Detailed methods and results
Discussion
Summary and conclusions
Author: H. F. Fraser, , H. Isbell
Pages: 29 to 43
Creation Date: 1961/01/01
This drug, hereinafter designated R-1132, is a congener of meperidine, and was developed by Janssen & Jageneau [ 1] . It has pronounced constipating and antidiarrheoal properties in mice, rats, dogs, cats, rabbits, and guinea pigs [ 2] , and in man [ 3] , small doses orally (2.5-5 mg several times a day with a maximum total of 30 mg daily for adults) are effective for this purpose. It does not possess analgesic activity for mice or rats by subcutaneous injection, and the constipating activity is not antagonized by nalorphine [ 2] .
Thus it appears that, at least in animals, a disssociation between two of the characteristic actions of opiate-like drugs (analgesic and constipative effects) has been achieved with the synthesis of R-1132. This suggested the possibility that R-1132 might also differ from other opiate-like antidiarrhoeal agents with respect to addiction liability, and that, if the latter were significantly less, R-1132 might be used to advantage when an opiate-like drug is indicated in the control of diarrhoea. Therefore, the human addiction liability of R-1132, relative to that of morphine and codeine, was evaluated in a series of experiments with emphasis on the oral route of administration of these drugs.
The subjects used in these studies were healthy adult white or negro males with previous histories of opiate addiction of long duration, who were serving sentences for violation of state or federal narcotic laws, and who volunteered for the experiment.
The tests employed included the following procedures: (i) administration of single graded doses for the detection of morphine-like subjective (euphorogenic) effects and/or morphine-like behaviour, (ii) substitution of R-1132 orally for morphine, in relatively large doses for 24 hours or 10 days, in patients addicted to morphine to ascertain its effectiveness in preventing symptoms of abstinence, (iii) "direct addiction ", which involved administration of these drugs in high or else progressively increasing doses as tolerated for 5, 18 or 60 days, followed by abrupt withdrawal to ascertain the presence and degree of physical dependence, and (iv) an attempt to precipitate abstinence phenomena by administration of nalorphine subcutaneously after 30 to 40 days of chronic intoxication with R-1132. For convenience in presentation, the specific details of methods and results will be described for each experiment.
Methods. In a preliminary study using seven patients, it was ascertained that in a dose range of 2-20 mg the effects of R-1132 could not be distinguished from those of a placebo. A cross-over experiment, using ten patients, was then set up to compare more quantitatively the effects of R-1132 (20 mg/80 kg) with those of morphine (20 mg/80 kg) and a placebo, employing the method of Fraser et al [ 4] . Three conditions were used: (i) R-1132 orally plus a subcutaneous placebo, (ii) an oral placebo plus morphine sulfate subcutaneously; and (iii) an oral and subcutaneous placebo. Two pre-drug and several post-drug observations were made at hourly intervals for seven successive hours. Measurements included rectal temperature, respiratory rate, respiratory minute volume, diameter of pupil, pulse rate and blood pressure. Patients were questioned concerning the subjective effects induced by the drug, and were observed for signs of morphine-like intoxication, including the incidence of vomiting. Differences between drugs were evaluated by the paired t-test.
Results. After R-1132 orally plus a placebo subcutaneously no opiate-like subjective effects were reported, and no opiate-like changes in behaviour were observed. In these doses, the effects of R-1132 on the variables measured were not significantly different from those of a placebo. After morphine subcutaneously plus an oral placebo, characterstic morphine-like effects developed.
Methods. This was a double-blind experiment in which 14 non-tolerant former opiate addicts served as subjects. Identically appearing capsules were administered at 7.30 a.m. while patients were fasting. All subjects received at weekly intervals in a randomized order the following medications: placebo capsules; morphine sulfate, 20 and 30 mg; codeine sulfate, 60 and 90 mg; and R-1132, 40 and 60 mg.
Observations were made immediately before, and one, two, three, four, six, eight, ten, twelve and fourteen hours after administration of the capsules.
Number of patients (of 14) responding a |
||||||
---|---|---|---|---|---|---|
Drug |
Dose (mg) |
Positive, opiates |
Positive, other drug |
Questionable |
Negative |
Average b total responses |
Placebo
|
-
|
1 | [1]c | 1 | 12 | 1.4 |
Morphine
|
20 | 7 | 1 [1] | 3 | 3 | 11.1 |
Morphine
|
30 | 7 | 2 | 3 | 2 | 11.9 |
Codeine
|
60 | 5 | 1 [1] | 4 | 4 | 6.0 |
Codeine
|
90 | 6 | 1 | 5 | 2 | 9.5 |
R-1132
|
40 | 4 | 2 [1] | 5 | 3 | 11.1 |
R-1132
|
60 | 11 | 1 [1] | 2 | 0 | 16.9 |
For method of scoring, see reference No. 5.
See reference No. 5 for method of obtaining these figures.
Figures in brackets represent patients who also reported positively for opiates.
At these times, both patients and aides completed a questionnaire designed to quantify both the subjective effects of the drugs as reported by the patients, and the changes in behaviour as observed by the aides [ 5] . The data obtained with this questionnaire were analysed as previously described [ 5] .
Results. The data on the subjective effects of morphine, codeine and R-1132 are summarized in table 1. It is noteworthy that eleven of the fourteen patients reported the subjective effects of 60 mg of R-1132 were opiate-like, whereas only seven of fourteen so reported after 90 mg of codeine. As judged by this criterion, 60 mg of R-1132 orally is a more effective "euphoriant" than 30 mg of morphine or 90 mg of codeine. The negligible response to placebo should also be noted. Although good dose-effect curves were not obtained (table 1), it appears that R-1132 is roughly one-half as potent as morphine in this respect, and is roughly 1.5 times as potent as codeine.
Methods. The purposes of this experiment were: (i) to ascertain if tolerance developed when R-1132 or codeine was administered in a euphorogenic dose once weekly for three successive weeks, and (ii) to determine the relative potency of single oral doses of R-1132 and codeine, utilizing a new subjective questionnaire for patients and a parallel, but separate, behaviour questionnaire for observers.
Eight non-tolerant patients were used in a double-blind test as follows: At weekly intervals, four subjects received three identical oral doses of codeine phosphate (140 mg), a placebo on the fourth week, followed by three successive weekly doses of 70 mg of R-1132. The other four patients received the same dosages of drugs with the sequence reversed. One week after each patient received his last dose of drug, each was given 10 mg of nalorphine subcutaneously [ 4] (latter was studied, because in monkeys [ 6] nalorphine-precipitated abstinence could be demonstrated as long as two or three weeks after the subcutaneous injection of one very large dose of R-1132).
Observations made were immediately before and one, two, three, four, six, eight, ten, twelve and fourteen hours after administration of the capsules at 7.30 a.m. At these times the patients completed a "single dose attitude" questionnaire for opiates (patients' ratings) consisting of the following: "Do you feel the medicine?" "This drug is most like what drug listed below (check one):a blank, dope (opiates), cocaine, marihuana, goof balls (barbiturates), benzedrine ("benny"), other "; "Check each sensation which you feel: normal, turning of the stomach,* skin itchy,* relaxed,* coasting,* soap-box,* pleasant sick,* sleepy, drive,* nervous, drunken, other"; "My liking for this drug is most nearly described by which of the following: not at all, slight, moderate, a lot, an awful lot, other", and "Comments". Responses to the question respecting degree of "liking for the drug" were graded on a weighted basis from 0 for "not at all", to 4 for "an awful lot," hence the minimum score for nine observations would be 0, and the maximum score 36. Symptoms marked with an asterisk were classified as specific for opiates, while other symptoms were considered to be relatively non-specific, since they are frequently reported after administration of drugs of other classes (e.g., barbiturates, alcohol, amphetamine).
For purposes of presentation, responses relating to the "specific" subjective and behavioural effects of the three drugs and placebo were classified under three headings: (i) identification as "dope" (opiates), (ii) incidence of opiate symptoms, and (iii) a weighted "attitude" score, representing the over-all preference for or aversion to each of the medications.
Concurrently and independently the observers completed the parallel questionnaire in which drugs were evaluated on the basis of the patient's behaviour. In addition, the diameter of the pupils in a controlled lighted room was recorded as in the previous experiment.
Both patients and aides were instructed to check only items observed since the last hourly observations, and if the words listed were not satisfactory, to insert others considered more appropriate or to make comments.
Results. When the results of the 8 subjects were averaged there was no significant change in successive weeks for either R-1132 (70 mg) or codeine (140 mg), indicating that on this regimen no significant tolerance to these effects developed. The total response curves (TRS) for the entire 14 hours for these variables are shown in figure 1. The TRS values for positive attitude scores and the incidence of opiate symptoms are similar for R-1132 and codeine. The TRS values for identification as "dope" are greater, but not significantly so for R-1132 as compared with codeine. These values are consistently low for a placebo, and none of the subjects at any time identified the placebo as "dope". With these doses of R-1132 and codeine, the peak value for all measurements is similar. The outstanding difference between R-1132 and codeine is in the time course. Peak effects of codeine were registered in every instance one to two hours after medication, whereas peak effects of R-1132 were from four to six hours after medication; the difference was statistically significant at the end of the first hour in the case of opiate symptoms and pupillary diameter. As noted in figure 1, the effects of R-1132 persisted longer than did those of codeine. When 10 mg of nalorphine was given one week after the last dose of codeine or R-1132, only the anticipated nalorphine effects per se and no signs of abstinence were observed. The results of this experiment confirmed those of the previous one on the comparative effects of single doses of R-1132 and codeine, and, in addition, they suggest that the relative potency of R-1132 may be somewhat greater than that indicated in experiment 2.
Effects of single oral doses of R-1132 (70 mg), codeine (140 mg) and a placebo respecting (i) identification as dope (maximum number of positive answers hourly = 1); (ii) incidence of opiate symptoms (maximum possible positive answers hourly = 7.0); (iii) attitude score (maximum possible hourly score = 4.0); and (iv) decrease in pupillary diameter. Each point on each curve represents the average of data obtained on eight men, each of whom had R-1132 and codeine three times and a placebo once. "TRS" values represent the mean areas (total response scores for 14 hours) ± standard areas of the means. The letter "S" on the codeine curve indicates that this point is significantly different from a corresponding point on the R-1132 curve, and illustrates the more rapid onset of effects of codeine as compared to those of R-1132.
Methods. R-1132 is extremely insoluble in water and most organic solvents, and for these tests it was necessary to dissolve it in pure propylene glycol and administer with a dry syringe. In a preliminary study, doses in the therapeutic range (2-15 mg) induced no detectable effects in ten tests using non-tolerant former opiate addicts. Higher doses were therefore given as follows: 30 mg (3 patients) and 50 mg (7 patients). Observations were made at intervals as described in experiment 3. In order to rule out interfering effects of the vehicle, two patients were given 20 mg of morphine sulfate dissolved in pure propylene glycol and similarly observed. In addition, an attempt was made to precipitate abstinence phenomena with 10 mg of nalorphine in three patients: in one, four days, and in two, six days after they received single doses of R-1132 (50 mg).
Average effects of single subcutaneous doses of R-1132 (30 and 50 mg) and of morphine sulfate (20 mg).All drugs were dissolved in pure propylene glycol.
Results. In doses of 2-15 mg (ten tests) and even in a dose of 30 mg (three tests), R-1132 induced no detectable effects, but in a dose of 50 mg, minimal effects were observed (figure 2). On the other hand, when 20 mg of morphine was dissolved in propylene glycol and injected subcutaneously, a complete pattern of morphine effects developed (figure 2). After nalorphine, no abstinence phenomena were precipitated.
Methods. In a preliminary study, doses of 5, 10 and 15 mg of R-1132 dissolved in pure propylene glycol provoked no definite effects in three tests on non-tolerant subjects. Higher doses were therefore given as follows: 30 mg (three patients) and 50 mg (seven patients). Observations were made at intervals, as described in experiment 3.
Results. In doses of 30 mg, R-1132 produced mild but definite opiate-like effects, and when the dosage was increased to 50 mg very definite and characteristic symptoms of morphine-like intoxication were observed (figure 3). The principal difference between R-1132 intravenously and,heroin or morphine was that the onset of effects after R-1132 was very gradual and no definite identification of opiate-like effects were made until about 10 to 20 minutes after injection; however, after 30 minutes the effects were pronounced (figure 3).
Average effects of single intravenous doses of 30 and 50 mg of R-1132 (dissolved in propylene glycol). "TRS" values represent the mean areas (total response scores for 14 hours) ± standard errors of the means.
Although not presented in the figure, the changes in behaviour recorded by the aides corresponded closely to those reported by the patients, and both of these paralleled the changes observed in pupillary diameter with respect to both time course and intensity of effect (figure 3).
Methods. Two different experiments were done at different times. In the first, ten patients who had been stabilized on an average of 240 mg of morphine sulfate subcutaneously daily received 150 to 200 mg of R-1132 (average 182 mg), divided into four or five oral doses, during the 24-hour substitution period. In the second experiment, five patients who were addicted to and stabilized on 240 mg of morphine sulfate daily received 30 mg of R-1132, six, fourteen and eighteen hours after their last dose of morphine (total dose during the substitution period being 90 mg). For comparison, data were available on nine patients (all of whom received R-1132 in the first substitution experiment) who received on three separate occasions 18, 36 and 90 mg of morphine (10, 20 and 50 per cent of their accustomed dose of morphine) during similar 24-hour substitution tests [ 5] .
Dose effect curves were constructed from the mean point hour scores after two dose levels of R-1132, and three dose levels of morphine. Regression lines, relative potencies, and 95% confidence limits were calculated according to the method of Bliss [ 7] .
Results. R-1132 proved to be an effective supressor of abstinence from morphine. The degree of suppression observed in the first experiment could not be distinguished from the degree observed after 50% of the usual dose of morphine. The dose-effect curve obtained is shown in figure 4. As indicated in the figure, 1 mg of morphine subcutaneously was calculated to equal 1.8 mg of R-1132 orally, with 95% confidence limits of 0.58-3.27 mg with respect to potency in suppressing abstinence from morphine. *
Dose-effect curves and relative potency for suppression of abstinence from morphine by R-1132 and graded doses of morphine; 24-hour substitutions in addicted individuals stabilized on 240 mg of morphine per day.
Methods. This was evaluated in five patients, each of whom had been stabilized on 240 mg of morphine sulfate daily, and had been addicted for 107, 153, 188, 189 and 201 days. Morphine was abruptly discontinued in all patients and replaced by 180 mg of R-1132 divided in approximately four equal doses daily. After ten days of substitution, R-1132 was abruptly discontinued and no therapy given. Intensity of abstinence was measured by the daily point score of Kolb & Himmelsbach [ 8] .
Results. R-1132 suppressed symptoms of abstinence from morphine very satisfactorily, but not completely. The maxi-mum intensity of abstinence observed was 10.5 points on the second day, otherwise the abstinence scores were not much greater than those which might have been anticipated had morphine been continued in the same patients (figure 5). In fact, the degree of abstinence-suppression by R-1132 observed in the present study exceeded that effected by codeine in an earlier study [ 9] , the results of which are also shown in figure 5. The very severe abstinence syndrome which follows when morphine addiction is untreated is illustrated in this same figure by the data obtained by Himmelsbach [ 10] . While receiving R-1132, one subject missed three doses during the ten days, and the explanation he gave was as follows: "I was practicing my horn and just forgot to come and get my medicine." Two other patients missed one dose of medication each during the ten days. None of these five patients missed any of their morphine injections during the prolonged addiction. All patients stated that R-1132 prevented the development of significant symptoms of abstinence, but each stated that" it did not feel like dope." This may be contrasted with consistent identification of opiate-like effects by the patients when codeine (average of 1,500 mg per day) was substituted for morphine [ 9] . When R-1132 was abruptly discontinued a mild but characteristic syndrome developed and the average peak intensity was 18.2 daily points. When codeine (1,500 mg) was substituted for morphine (260 mg) for 14 days in the experiment described by Fraser & Isbell [ 9] there was a much greater rise in abstinence scores to a peak of 34 points on the second day after withdrawal of codeine (figure 5). Although the number of cases in which R-1132 was substituted for morphine is small, the experiment indicates that, in equivalent abstinence-suppressing doses, orally administered R-1132 is less effective than codeine in producing morphine-like subjective effects in addicted patients, and that it produces less physical dependence than codeine after substitution for morphine for a period of ten days.
In corresponding substitution tests, it was ascertained that 1 mg morphine subcutaneously is equivalent to 2.86 mg of morphine orally, and to 13.7 mg of codeine orally (unpublished data of Fraser, Wolbach & Martin).
Methods. This was evaluated in five initially non-tolerant subjects who were addicted from 45 to 61 days in a dosage outlined in table 2. The usual plan in such experiments is to increase the dose of the drug as rapidly as possible during the first 18 days of addiction, and then to continue medication at the dosage attained for an additional 40 to 70 days. However, since uncomfortable gastro-intestinal complications might occur on such a schedule in the case of R-1132, the dosage of this drug was increased much more gradually than is usually the case, using as a guide its effectiveness in causing constipation and the absence of toxic symptoms. In order to obtain data on the frequency of stools and necessary laboratory data, all subjects were examined for a considerable time without drugs. Observations during pre-drug, medication, and withdrawal phases included weight and caloric intake daily, and temperature, pulse, respiratory rate and blood pressure three times daily. Special observations included number of stools daily, hours of sleep, hours of inactivity, and hours of activity, all of which were recorded at half-hour intervals daily. Inactivity refers to hours spent on bed in a horizontal position, and was recorded as positive whether or not the patient was sleeping. Activity refers to the hours a patient was out of the ward - i.e., when he pursued either work or recreational activities outside the research unit. Laboratory observations were made at intervals of two weeks and included urinalyses (including tests for bilirubin), red-blood-cell count, white-blood-cell count, hemoglobin, hematocrit, sedimentation rate, and two liver function tests (bilirubin content of serum and cephalin flocculation tests). R-1132 was abruptly discontinued after an average of 57 days, and identically appearing placebo capsules were substituted. In order to ascertain whether patients could differentiate the subjective effects of R-1132 from those of a placebo, it was carefully explained to the patients that placebo capsules would be substituted during the next few days, at a time unknown to both patients and observers. They were requested to notify observers when they thought placebo capsules had been substituted for capsules containing drugs. Intensity of abstinence following withdrawal of R-1132 was evaluated by the Kolb & Himmelsbach [ 8] daily point score.
Average intensity of abstinence recorded in daily point scores of five patients while stabilized on 240 mg of morphine daily; when morphine was discontinued and R-1132 substituted in an average dosage of 180 mg daily; and the intensity of abstinence when R-1132 was discontinued abruptly. These scores are compared with the average scores often subjects in another experiment (Fraser & Isbell), when codeine was substituted for morphine and when codeine was withdrawn. These are also compared with the intensity of abstinence in 65 untreated cases reported by Himmelsbach.
Days |
Daily dose |
Wt. last day |
Resp ./ Min. |
Hours sleep |
Hours inactive |
Hours active |
Average daily stools |
|||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
Subject |
Pre-drug |
R-1132 |
Initial |
Maxi-mum |
Pre-drug |
R-1132 |
Pre-drug |
R-1132 |
With-drawal |
Pre-drug |
R-1132 |
With-drawal |
Pre-drug |
R-1132 |
With-drawal |
Pre-drug |
R-1132 |
With-drawal |
Pre-drug |
R-1132 |
(mg)
|
(mg)
|
(kg)
|
(kg)
|
|||||||||||||||||
CEP
|
33 | 59 | 45 | 285 | 65.60 | 69.65 | 16 | 15 | 15 | 7.75 | 8.26 | 7.00 | 11.76 | 11.90 | 8.06 | 5.00 | 2.32a | 4.95 | 1.42 | 1.07a |
SIM
|
39 | 59 | 50 | 215 | 95.68 | 98.20 | 23 | 19a | 19 | 7.15 | 4.50 | 9.35 | 10.76 | 8.00 | 12.55 | 2.48 | 0.87a | 2.75 | 0.95 | 0.61a |
MOO
|
35 | 45 | 50 | 155 | 62.90 | 63.22 | 22 | 22 | 24 | 7.80 | 8.13 | 5.30 | 10.55 | 11.60 | 10.05 | 3.75 | 2.72a | 4.35 | 0.86 | 0.21a |
RIC
|
14b | 60 | 20 | 105 | 56.80 | 59.00 | 18 | 15a | 19 | 5.71 | 6.75 | 6.45 | 9.00 | 11.00 | 10.20 | 1.75 | 1.27a | 2.35 | 1.07 | 0.47a |
WAS
|
24 | 61 | 45 | 180 | 84.90 | 82.30 | 19 | 16a | 18 | 6.77 | 7.99a | 7.40 | 10.60 | 11.30 | 11.15 | 6.52 | 4.12a | 5.60 | 1.00 | 0.56a |
Average
|
29 | 57 | 42 | 188 | 73.18 | 74.47 | 19.6 | 17.4 | 19 | 7.04 | 7.13 | 7.10 | 10.53 | 10.76 | 10.40 | 3.90 | 2.26 | 4.00 | 1.06 | 0.58 |
a Significantly different (0.05) as compared with control observations; computations were made using the same individual as his own control.
b Post-drug, tenth to twenty-fourth day after R-1132 discontinued.
Results. All subjects reported that R-1132 induced constipation similar to that caused by opiates. The average number of stools per day was 1.06 prior to R-1132, and 0.58 while on R-1132. One subject (CEP) was quite resistant to the constipating effect despite a progressive rise in dosage to 285 mg of R-1132 daily (table 1). One subject (RIC) reported some difficulty in urination and occasional nausea during the early part of the experiment. All subjects reported that they could go to sleep more readily, and in four of the five subjects hours of sleep were increased while on the drug. Every subject showed a reduced number of hours out of the ward (activity). All subjects consistently denied opiate-like, subjective effects such as those experienced during the early phases of addiction to morphine (injected subcutaneously) or oral methadone. R-1132 significantly depressed the respiratory rate in three of five subjects (table 2). In the dosage schedule employed, R-1132 did not affect rectal temperature, pulse rate or blood pressure.
Four of the five patients erroneously reported that placebo capsules had replaced R-1132 from one to three days prior to the actual day when placebos were started. The fifth patient stated the incorrect day, but amended his statement on the following day, correctly stating he was still receiving R-1132. However, when placebo capsules were actually started, four patients who developed significant symptoms of abstinence then were certain that placebos had been given. In other words, they could not evaluate accurately, from the subjective effects induced, whether or not they were receiving R-1132, but were able correctly to identify subjective effects of abstinence from R-1132.
Urinalyses, blood counts and liver function tests showed no abnormalities during maintained addiction. In the three subjects tested for precipitation of abstinence with nalorphine, a positive result was recorded in every case, but this was considered to be somewhat milder than would have been anticipated for a corresponding period of addiction to morphine.
Average intensity of abstinence ( daily point scores) of five patients when R-1132 was discontinued abruptly after 45 to 61 days of chronic administration. The average maximum dose maintained was 188 mg daily. These scores are compared with the average scores of eight men in another experiment, who were chronically maintained on an average of 1,550 mg of codeine daily, and after 60 days the codeine was withdrawn abruptly [ 11] .
After R-1132 was discontinued, four of the five subjects developed a relatively mild, but definite and characteristic, abstinence syndrome. The average intensity of abstinence for these five subjects during the first ten days after R-1132 was withdrawn is illustrated in figure 6, and may be compared with the intensity of abstinence observed when codeine was abruptly withdrawn after 60 days of addiction [ 11] .
Methods. Eight non-tolerant subjects were used, each to be exposed to all drugs. Three of these, CEP, WAS and MOO, were subjects in the previous study of chronic intoxication with R-1132. Morphine sulfate and codeine sulfate served as positive controls and starch capsules, flavoured with quinine, were the negative control. Four other drugs were included in this test, but they are not pertinent to this study [ 12] . Each drug except the placebo was given orally in progressively increasing dosage, starting on the first day with a dosage one to two times the" maximal therapeutic " dosage, and ending on the eighteenth day with a dosage which approximated seven to ten times the initial dosage. The dose attained on the eighteenth day was given each patient on the nineteenth or twentieth day.
All drugs were discontinued in a randomized order on the eighteenth, nineteenth or twentieth day, and each was replaced with a placebo given at the usual time and in the usual form, quantity, and customary volume. After ten days of abstinence, each patient received another drug in the sequence.
The initial daily dosage of morphine was 32 mg, and the maximum dosage attained was 240 mg daily. Codeine was started with a dosage of 200 mg daily, and was increased to a maximum of 1,500 mg per day. No difficulty was encountered in increasing the dosage of either to these levels in any patient. The starting dose of R-1132 and the maximum attained varied (see table 3).
Observations and laboratory tests were the same as those made in the "long" addiction test, except that no record was kept of the number of stools passed.
The attitude of the patients toward the drugs administered was ascertained daily at 7 p.m. by the responses to a special "chronic dosage attitude" questionnaire for opiates (patients' ratings), which each completed without assistance. The questions asked were as follows:" Has this drug produced any effect on you?" "Does this drug feel like an opiate (dope)?" "If so, is it most like: heroin, morphine, codeine, other dope-like drug (please name);" and its "strength" is: "no effect, very weak, weak, average, strong, very strong, overdose;" or "is the feeling from this drug like one of the drugs given below: a blank (water), marihuana (reefer), cocaine, barbiturates (goof balls), alcohol (whiskey or beer), benzedrine (benny), other drug (please name);" and its "strength" is: "no effect, very weak, weak, average, strong, very strong, overdose;" "Would you like to take this drug every day?" Alternative answers listed were: "Yes," "No," and "Don't care." "Does this drug make you feel bad? If so, does it make you feel so badly that you would stop taking it if you were not on a test?" Describe briefly the most important effects of the drug ou you;" and" "Are you kicking a habit?" It was impressed upon the patients that the physicians and observers did not care whether the patients liked, disliked or were indifferent about any particular drug, and that the primary purpose of the questionnaire was to obtain as accurately as possible the attitude of the patient toward each drug.
Concurrently and independently at 7 p.m. daily, the aides, each of whom had a minimum of six years' continuous experience on the research ward, completed a parallel "attitude questionnaire" (observers' ratings), except that the queries were couched in terms of behaviour; for example, "Does this patient show behaviour resembling that seen after opiates?" Prior to completing the questionnaire, each aide was instructed not to consult the current questionnaire completed by the patient, but he could review the notes of any other observer, could take into consideration the opinion expressed by any other aide, and could review the previous answers of the patient to the questionnaire. He was instructed specifically, however, not to hesitate to give his opinion of the effect of the drugs, even though it might be different from that of the subject.
For purposes of presentation, the ratings of both patients and aides were classified under four general headings: (i) any drug effect, (ii) identified as "dope" (or behaviour like after "dope"), estimate of "strength of drug" (or estimate of potency), and (iv) "would like to take daily?" and scores were computed on the basis of frequency of response.
Results. Each of the eight patients completed the entire test on all drugs, except one patient, who quit the test after having received seven of the eight drugs, stating that the "drive" while on drugs was insufficient to compensate for the degree of abstinence which developed. It happened that R-1132 was the eighth drug which this patient was scheduled to take, and hence only seven patients received R-1132 chronically during this study. In the case of morphine and codeine, no difficulty was encountered in progressively raising the dosage according to plan. However, in the case of one patient receiving R-1132, the dosage was progressively elevated to 160 mg by the eleventh day, but the patient became so sedated (spending 18 to 22 hours horizontal in his bed daily) that it was decided not to increase the dosage further until the patient showed some significant evidence of tolerance. Since he continued to be highly sedated, no further attempt was made to augment his dosage during the remainder of the test.
Subject |
Days on drug |
Initial dose (mg) |
Maximum dose (mg) |
Total dose (mg) |
---|---|---|---|---|
GR
|
20 | 40 | 300 | 3,300 |
CEP
|
20 | 40 | 300 | 3,320 |
WA
|
19 | 64 | 480 | 4,954 |
WAS
|
18 | 40 | 300 | 2,720 |
MOO
|
19 | 64 | 480 | 4,954 |
BR
|
19 | 40 | 160 | 2,320 |
SU
|
20 | 60 | 400 | 4,890 |
While receiving medication, all these patients showed constriction of the pupils, considerable sedation, constipation, and some pruritus. There was also nausea in several patients, but neither nausea nor vomiting was conspicuous, despite this progressive increase in dosage.
The average effects of R-1132, codeine and morphine as compared with those of a placebo on respiratory rate, systolic blood pressure, rectal temperature, hours of sleep, hours of activity, and hours of inactivity are shown in table 4. It is apparent that all of these drugs depressed respiratory rate significantly to approximately equal degrees, and tended to increase inactivity. None of the drugs affected significantly systolic blood pressure, rectal temperature, hours of sleep per day, or initiative activity. The results obtained with the questionnaires (figures 7 a and 7 b) represent average responses on a percentage basis from the total of 134 in the case of R-1132 (N = 7), and 154 in the case of morphine, codeine and pla-cebo (N = 8). Patients recognized some drug effect about 50% of the time when morphine, codeine and R-1132 were given. It is remarkable, since the study was conducted "double-blind ", that in no instance did the patients state a placebo produced any drug effect.
Drug |
Resp. rate |
Systolic B/P |
Rectal temp., °C |
Sleep hours |
Activity hours |
Inactivity hours |
---|---|---|---|---|---|---|
Placeboa
|
18.8 | 109.7 | 37.03 | 7.08 | 3.34 | 10.35 |
R-1132
|
14.6b | 105.8 | 37.08 | 7.74 | 2.79 | 12.50c |
Codeine
|
14.5b | 107.6 | 36.96 | 6.88 | 3.93 | 11.23 |
Morphine
|
15.1b | 106.3 | 37.00 | 7.16 | 3.15 | 11.00 |
a Each patient was on a placebo for 30 consecutive days, but his tabulation covers only the first 20 days on placebo.
b Value is significantly different from that observed when a placebo is given. The paired "t" value comparing R-1132 and a placebo is 6.20; comparing codeine with a placebo is 6.00; and comparing morphine with a palcebo is 10.6.
c Value is significantly different from that observed when a placebo is given; "t" = 2.55.
Summary of results of questionnaires prepared by aides when they evaluated the effects of morphine, codeine, R-1132, and a placebo on the basis of the patients' behaviour during the 18-20-day "double-blind" direct addiction study (experiment 9).
Although aides considered that all drugs possessed opiate characteristics to quite a high degree, it would appear that both patients and aides thought R-1132 was less opiate-like than morphine and codeine. In fact, patients were much more impressed by the sedative characteristics of R-1132 than its opiate qualities. For example, one patient (MOO), who contributed 70% of the "yes" answers to the question, "feels like opiates (dope)" (figure 7 a), positively identified R-1132 in the non-opiate category concurrently, and in response to the question, "type of dope", he wrote in "goof balls" (barbiturates) every time.
Intensity of abstinence, as indicated by the daily point and TAS-10 scores, is shown for morphine, codeine and R-1132 in figure 8. These were compared with the intensity of abstinence observed when a placebo was the "drug of addiction". Intensity of abstinence after withdrawal of R-1132 was only slightly less than that observed after withdrawal of codeine, but significantly less severe than that observed after withdrawal of morphine (P = < 0.001). The over-all pattern of withdrawal from R-1132 and codeine was similar, and the abstinence syndrome in each instance was mild. Intensity of abstinence as previously described was computed by two procedures: the standard procedure of Himmelsbach, using as a baseline the last seven days on drug, and a modified procedure of Himmelsbach, in which the baseline was established by 30 days on placebo [ 12] .
The results of this short-term direct addiction test confirm those of the preceding "long" addiction study, and demonstrate that continuous administration of R-1132 is associated with a low incidence of morphine-like subjective effects (reported by the patient), but with definite morphine-like changes in behaviour (rated by the aides), and is associated with the development of a moderate degree of physical dependence. Although the average daily maximum dosages attained for morphine (240 mg), codeine (1,500 mg) and R-1132 (343 mg) represent equivalent intoxicating doses (respiratory depression and/or sedation), they are not equivalent dosages from the viewpoint of suppressing morphine abstinence (figure 4), since the maximum daily dosage of morphine and codeine necessary to produce a comparable relief of the abstinence syndrome afforded by 343 mg of R-1132 would be respectively 544 mg of morphine and 2,600 mg of codeine.
Comparative intensity of abstinence after abrupt withdrawal of morphine, codeine, R-1132, and a placebo ( experiment 9) . Daily point scores were computed by using the averages for rectal temperature, respiratory rate, blood pressure, and caloric intake observed during the last seven days of addiction ( standard Himmelsbach method) for the baseline, and also by using the averages observed during 30 days on placebo ( modified Himmelsbach procedure) . The TAS-10 values represent the mean areas ( total intensity of abstinence for 10 days) ± the standard error of the means. "t" values refer to the significance of the difference in the degree of abstinence observed with each drug as compared to that ascertained when the placebo was considered to be the "drug of addiction". An asterisk indicates that the difference is highly significant.
As compared with pre-drug values, chronic administration of R-1132 did not produce any significant changes in white-or red-blood-cell counts, differential white-cell counts, hematocrit, sedimentation rates or urinalysis. There were no significant changes in body weight.
Methods. Since, in the case of drugs with low euphorogenic otency, addicts would not be likely to utilize a gradual increase in dosage, but would attempt to use doses which would provoke morphine-like euphoria, it was thought desirable in one experiment to use doses which were euphorogenic initially and to continue this dosage for five days. For comparison, not only R-1132 and codeine, but two other drugs were studied. All of these were administered orally in identically appearing capsules, and in a randomized schedule. The daily dosage was as follows: d-methadone (900 mg), d-3-methoxy-N-phenethylmorphinan (2,000 mg), R-1132 (240 mg), and codeine phosphate (480 mg). All patients received capsules four times daily, but, because of their greater length of action, d-methadone and R-1132 were given in only three equally divided doses rather than four.
Summary of the results of patients' questionnaires in a "short" direct addiction test ( experiment 10) , when patients received for five successive days "euphorogenic" oral dose levels of R-1132 and codeine phosphate. These are compared with results reported after a placebo given for ten consecutive days.
The schedule provided for ten days' pre-drug observations during which placebo capsules were given on a four-per-day schedule, and then five days of medication followed by ten days on placebo until all drugs were administered. Patients were unaware of the drugs to be given or their sequence of administration, but were advised that certain of the drugs might induce toxic symptoms, and that the patient could voluntarily discontinue any drug at any time. All observers knew the complete schedule and were instructed to discontinue any medication and/or administer nalorphine promptly should any serious symptom of intoxication develop. Observations were made daily as enumerated for the "short" (18 to 20 days) direct addiction test, including the completion of "subjective" and "behavioural" questionnaires.
Results. Under these conditions the response of the patients differed greatly from that observed when the dosage was gradually accelerated. In the four subjects used, codeine was always identified as "dope", R-1132 was so identified 19 out of 20 times, and placebo was identified as "dope" once during the pre-drug period of ten days, or once in 40 times (figure 9). The incidence of non-narcotic symptoms was greater for R-1132 than for codeine, and the estimates of strength were much higher than that reported in the previous experiment. In the case of the other two drugs, toxic symptoms developed in certain patients and it was necessary to terminate the medication before the five days had been completed. It was not necessary to discontinue either codeine or R-1132 on this account. It may be concluded that when R-1132 was administered on a temporary "euphorogenic" schedule the patients' liking for the drug was comparable to that of codeine.
Abuse liability, as pointed out by Isbell [ 13] , depends on a multiplicity of factors and includes the quality of euphoric effects induced, the speed of onset and duration of that effect, presence or absence of side effects regarded as undesirable or desirable by the addict, ability to suppress abstinence, intensity of the abstinence syndrome at its peak after withdrawal, duration of the abstinence syndrome, and the ability to continue use of the drug either intravenously or subcutaneously. Furthermore, there are considerable variations in addictiveness, not only among drugs but among preparations of the same drug, depending on whether they are suitable for injection or for oral administration only. For example, of 45,957 addicts reported during 1955-1959 in the United States, only 155 were addicted to paregoric and 171 to codeine, but 1,396 were addicted to morphine (Bureau of Narcotics, 30 September 1959). It is apparent that morphine has a low incidence of abuse when available as a mixed preparation for oral use (paregoric), and codeine also possesses low addiction liability despite the fact that it can be injected. Since the doses of morphine, codeine and R-1132 which were euphorogenic in these studies were from three to sixteen times those which would be employed clinically for controlling diarrhoea, it is apparent that addiction to any of these drugs is not likely to occur if given orally under strict medical supervision for this purpose. For example, in a series of 830 cases treated with R-1132 for diarrhoea of multiple etiology, reported by Janssen [ 3] , there was no evidence that any of the patients developed morphine-like euphoria, significant degrees of tolerance, or physical dependence. Additional evidence in support of these points is furnished from the report of Dr. Vander Stappen [ 14] .
However, R-1132 has abuse liability when administered in large doses orally and intravenously, because the subjective effects and behaviour observed resemble those seen after administration of morphine and codeine in the same patients, and because physical dependence develops on an abuse schedule.
The advantages of R-1132 as compared with those of morphine and codeine from the viewpoint of abuse may be outlined as follows: (i) R-1132 is very insoluble in water and, if compounded with inert ingredients for use as an oral preparation, addicts would be confronted with a major chemical extraction procedure if they tried to prepare an adequate amount for intravenous use; (ii) it would not be suitable for subcutaneous abuse; (iii) the onset of euphoria is slow by all routes of administration; and (iv) it induces less physical dependence than morphine, although it offers no advantage over codeine in this respect.
R-1132 exhibits greater abuse liability than d-propoxyphene, especially in respect to the properties of tolerance and physical dependence [ 9] .
1. Administration of single oral, sucutaneous, or intravenous doses of R-1132 in the therapeutic range did not induce morphine-like subjective effects or behavioural changes. However, in a dose range of from 40 to 60 mg R-1132 provoked definite morphine-like euphoria and behavioural changes by the oral and intravenous routes. When given subcutaneously in doses of 5 to 50 mg, only minimal effects were observed.
2. When substituted for morphine for 24 hours in addicted patients, it suppressed abstinence from morphine practically completely, and the dosage equivalence was considered to be 1 mg of morphine for 1.8 mg of R-1132.
3. When substituted for morphine for a period of ten successive days, R-1132 was slightly more effective than codeine in preventing the appearance of abstinence phenomena, but it was not identified as an opiate during the interval of substitution. Abrupt withdrawal of R-1132 resulted in a milder abstinence syndrome than that which occurs after abrupt withdrawal of codeine, following substitution of the latter in equivalent morphine abstinence-suppressing dosages.
4. Five patients received oral doses of R-1132 chronically for 45 to 61 days, and the dosage was gradually and carefully increased as tolerance developed until the average maximum dosage attained was 188 mg daily. In another "double-blind" cross-over study, eight patients received orally R-1132, morphine, and codeine, all given in a rapidly accelerated dosage for 18 to 20 days, and the effects were compared with a placebo. Objectively, especially on the more rapidly increasing dosage schedule of R-1132, the over-all pattern of behaviour resembled that of addiction to morphine or codeine, except that sedative effects were more prominent. In both of these tests, however, the patients were much more impressed with the sedative rather than the opiate characteristics of R-1132. When R-1132 was abruptly discontinued in both of these studies, a definite but mild abstinence syndrome developed, which was significantly less severe than that observed when oral morphine was withdrawn from the same patients, but comparable to the abstinence syndrome that ensued after abrupt withdrawal of oral codeine.
5. When R-1132 was administered chronically in high dosage, nalorphine precipitated a moderately severe abstinence syndrome.
6. When R-1132 and codeine were continuously administered in high and euphorogenic dosages at different times for five consecutive days, both drugs were identified consistently as an opiate (dope), and the effects of both drugs were liked by the patients.
It is concluded that R-1132 possesses abuse liability. Considering all the data available, it appears that this is definitely less than that of morphine and greater than that of d-propoxyphene. Although the abuse liability of R-1132 is comparable with that of codeine in several respects, the unsuitability of R-1132 for parenteral injection decreases the hazards that may attend its use in clinical practice.
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