METHODS
RESULTS
DISCUSSION
SUMMARY
Author: H. F. Fraser, Harris Isbell
Pages: 15 to 23
Creation Date: 1960/01/01
Interest in the addictiveness of phenazocine 4and levophenacylmorphan 5was aroused because both drugs were found to be more potent analgesics in mice [ 11] and man [ 4] [ 14] [ 10] [ 13] than morphine, but were far less potent than morphine in reducing the intensity of abstinence from morphine in addicted monkeys [ 3] . Thus, it seemed possible that a considerable dissociation in analgesic and abstinence-suppressing potencies (sometimes equated with "addiction liability ") had been achieved in these drugs. Studies on the human pharmacology, with particular emphasis on the addictiveness of both drugs, were therefore undertaken.
Drugs. - Drugs were given hypodermically, except that single doses of NIH-7519 and NIH-7525 were also evaluated by the intravenous route. NIH-7519 and NIH-7525 were dissolved in 25% propylene glycol in water in a concentration of 0.4 to 1%. Use of propylene glycol was necessary because of the low solubility of the drugs in water. Placebo consisted of the vehicle used to dissolve the drugs. Morphine sulfate was dissolved in distilled water to make a 2 to 5% solution. Weights of the drugs refer to the salts.
Subjects. - All subjects used in these experiments were males who were serving sentences for violations of the federal narcotic laws, and who volunteered for the experiments. All were physically healthy, and none presented evidence of the major psychoses. Those patients used in assessing the effects of single doses and in direct addiction experiments were abstinent from opiates (non-addicted, non-tolerant "former" addicts) at the time the experiments were begun.
Experiment 1. - Effects of Single Doses Subcutaneously
In preliminary experiments it was found that 2 to 3 mg of NIH-7525 and 3 to 4 mg of NIH-7519 induced subjective, behavioural and objective effects comparable to those caused by 20 mg of morphine subcutaneously. An experiment was then designed in which 12 to 17 subjects, who were unaware of the identity of the agents, received in a randomized fashion the following medications: placebo ( patients); 2 and 3 mg of NIH-7525 (17 patients); 3 and 4 mg of NIH-7519 (17 patients); and 8 mg (12 patients), 13 mg (17 patients), and 20 mg (16 patients) of morphine. The inequalities in the numbers in the various groups were due to expiration of eligibility of some of the patients for participation in experiments before all the doses could be completed.
1 dl-2'-Hydroxy-5,9-dimethyl-2-(2-phenethyl)-6,7-benzmorphan HBr, NIH-7519.
2 l-3-Hydroxy-N-phenacyl-morphinan methane sulfonate, NIH-7525.
3Observations reported in this article were taken into account by the WHO Expert Committee on Addiction-producing Drugs at its tenth session, in October 1959, when considering the question of international control of the drugs phenazocine and levophenacylmorphan (see, at the end of this volume, "Note: Changes in the scope of control ").
4Phenazocine was prepared in the laboratories of Smith, Kline & French according to the method devised by Dr. Everette L. May of the National Institutes of Health. The Smith, Kline & French code number is SKF-6754. The drug will be referred to throughout the paper by the code number of the National Institutes of Health, NIH-7519.
5 Levophenacylmorphan was supplied through Dr. Nathan B. Eddy by Hoffman-La Roche, Inc., Basle, Switzerland, under the code number Ro 4-0288-1. The drug will be referred to throughout the paper by the code number NIH-7525.
Immediately prior to and at hourly intervals after injection of the drugs, the diameter of the patients' pupils was measured in a dark room under conditions of controlled light and accommodation by comparing the size of the pupils with blackened circles of known diameter on a card. The patients remained in a special ward throughout the experimental period, and were observed by specially trained aides. Immediately before and at hourly intervals after administration of the drugs, the patients completed, with the help of aides, a simple questionnaire consisting of the following questions: "I feel the medicine; " " The feeling is like: morphine, marihuana, benzedrine, heroin, barbiturates;" "I don't feel anything;" "I am nervous; " "I am relaxed;" "I am nauseated;" "I am sleepy;" "I have a drive;" and "I would like more." The aides also filled out a questionnaire dealing with observable changes in behaviour which frequently occur after morphine and wrote supplementary notes as indicated.
The data were analysed in the following ways: Change in the size of pupil was obtained by subtracting the post-drug values from the pre-drug values. The area under the time-action curve composed of these changes in pupillary diameter was calculated by the method of Winter & Flataker [ 15] , thus converting all the data on a particular patient for a particular dose of a drug to one figure. Means and standard errors were calculated by standard statistical techniques. In addition, the mean change at each hour after administration of the drug was calculated in order to obtain time-action curves for the various doses of the different drugs.
The responses on the questionnaire were classified as follows: A response that the subjective effects were similar to morphine or heroin at any time during the observation period was scored "positive for opiates "; a response that the effects were similar to amphetamine, barbiturates, or marihuana was scored "positive for other drugs "; a response that subjective effects were present which were not regarded as similar to those of any drug listed in the questionnaire was scored "questionable "; denial of all subjective effects was scored "negative ". It was hoped that the responses classified in this way could be used to determine the" euphoric" potency of NIH-7519 and NIH-7525 by probit analysis, using "positive for opiates" as the primary criterion of the response; but, as will be seen in the results, the doses of NIH-7519 and NIH-7525 chosen were too high to yield good estimates by this method, so another method of analysis was tried. The total number of responses scored positively on the questionnaire (excluding responses to the questions "I don't feel anything" and "I would like more ") which were not scored positively before the drug were counted and the mean number of responses was calculated for each dose of each drug.
The means for the total number of questions and the areas under the curves for pupillary constriction were used in constructing dose-effect curves. Regression lines for these curves, relative potencies of NIH-7519, NIH-7525 and morphine, and 95% confidence limits were calculated by the methods described by Bliss [ 2] .
Experiment 2. - Effect of Single Doses Intravenously
NIH-7519 was administered intravenously in a dosage of 2 mg (3 patients); 3 mg (5 patients); and 5 mg (9 patients). NIH-7525 was given intravenously in a dosage of 0.5 mg (7 patients); 1.0 mg (10 patients); and 1.5 mg (4 patients). Some patients received both drugs, and some different dosage levels of the same drug. There was no comparison of effects of morphine given intravenously in the same subjects. The primary object of the experiment was to ascertain if an intravenous dose of both NIH-7519 and NIH-7525 could be given that would induce subjective and behavioural effects in post-addicts comparable to that of 20 to 30 mg of morphine sulfate similarly given. The questionnaire referred to under subcutaneous doses was completed at hourly intervals for eight hours after both drugs were given, and behaviour and pupillary diameter were concurrently recorded. Since, from the standpoint of abuse, the important points to be ascertained were similarity of the unknown drug to morphine or heroin and the intensity and duration of its effect, emphasis was placed on these aspects in tabulating the data (table 3).
Experiment 3. - Twenty-four-hour Tests for Ability to suppress Symptoms of Abstinence
Five patients who were addicted to and stabilized on 240 mg of morphine daily (divided into four doses) were used in these experiments. In each test, each patient received his last dose of morphine at 4 p.m., and was given no more morphine until 4 p.m. on the following day. During this period, each patient would normally receive three doses of 60 mg of morphine. Tests were conducted at weekly intervals with patients being returned to their accustomed doses of morphine between tests. The patients were not aware of the identity of the drugs under test. Each patient received in randomized fashion during various substitution periods a total dosage of 3, 6, and 9 mg of NIH-7519 and NIH-7525. Each dosage was divided among three equal doses. For comparison, data were available on 9 other patients who received in similar tests 18 mg (10 per cent of their usual dosage of morphine), 36 mg (20 per cent), and 90 mg (50 per cent) of morphine instead of the 180 mg of morphine they normally would have been given during the substitution period. Observations for symptoms of abstinence were made hourly from the fourteenth to the twenty-fourth hour (6 a.m. to 4 p.m.) after the last dose of morphine, and hourly point-scores of the intensity of abstinence calculated according to the system of Himmelsbach (8). The areas under the time-action curves composed of the hourly point-scores were calculated by the method of Winter & Flataker (15), yielding area figures (points multiplied by hours) termed "point-hour" scores. The mean figures for the various doses of NIH-7519, NIH-7525 and morphine were used in constructing dose-effect curves. Regression lines, relative potencies, and 95% confidence limits were calculated according to the methods described by Bliss [ 2] .
Experiment 4. - Substitution for Morphine for Ten Days
Five patients who were addicted to and stabilized on 240 mg of morphine daily were available for these experiments. In two cases, morphine was abruptly discontinued, and 32 mg of NIH-7519 daily (divided into four doses subcutaneously) was substituted for the morphine. In the other 3 patients, 24 mg of NIH-7525 daily was substituted for morphine. The dosages of NIH-7519 and NIH-7525 were chosen on the basis of the potencies of the drugs in suppressing abstinence from morphine in the 24-hour substitutions. After ten days of substitution, NIH-7519 and NIH-7525 were replaced with placebo injections. Throughout the phases of stabilization on morphine, substitution of NIH-7519 and NIH-7525, and abrupt withdrawal of the latter, observations for symptoms of abstinence were made three times daily, and the intensity of abstinence calculated in terms of daily point-scores according to the system of Kolb & Himmelsbach [ 9] . The area under the time-action curves for the first seven days following abrupt withdrawal of NIH-7519 and NIH-7525 was calculated, yielding a figure termed the TAS-7 (total intensity of the abstinence syndrome for seven days). The daily dosages of morphine corresponding to the TAS-7 scores for the individual scores were interpolated from the curve of Andrews & Himmelsbach [ 1] , which relates the intensity of abstinence from morphine, as reflected by the TAS-7 scores, to the daily dosage of morphine. In this way, a rough comparison of the intensity of abstinence following withdrawal of the substituted drugs with the intensity of abstinence after withdrawal of equivalent amounts of morphine can be made.
Experiment 5. - Preliminary "Short" Direct Addiction Experiments
These experiments were performed in order to obtain a preliminary idea of whether NIH- 7519 and NIH-7525 would produce physical dependence in man. One patient received NIH-7519 for 19 days with the daily dosage increasing as rapidly as tolerated, from 5 mg on the first day to 34 mg on the 19th day. Another patient received NIH-7525 for 19 days, the daily dosage increasing from 5 mg on the first day to 28 mg on the 19th day. Withdrawal of the drugs was abrupt and complete. Observations for symptoms of abstinence were made, and daily point-scores calculated according to the system of Kolb & Himmelsbach throughout the experiment, and for ten days after withdrawal of the drugs. Precipitation of abstinence by subcutaneous administration of 5 mg of nalorphine was attempted on the 16th day (NIH-7519) and 17th day (NIH-7525) of chronic drug administration, with observations for symptoms of abstinence being made at intervals of 15 minutes twice before and four times after the administration of nalorphine.
Experiment 6. - " Long" Direct Addiction to NIH-7519
One patient received NIH-7519 in dosages increasing from 5 mg daily (divided into four equal doses) to 60 mg daily on the 69th day. This level was maintained until the 127th day, after which NIH-7519 was replaced with placebos. A preliminary short withdrawal lasting 42 hours was carried out on the 24th to the 26th day, after which the patient was returned to the drug. Prior to this short period of withdrawal, the patient had attained a dosage of 24 mg daily, and when the drug was resumed he was begun on 24 mg daily. On the 18th day of addiction, when the patient was receiving 24 mg of NIH-7519 daily, abstinence was precipitated by the subcutaneous administration of 5 mg of nalorphine. Observations for symptoms of abstinence were made three times before and four times after (at intervals of 15 minutes) administration of the nalorphine. On the 77th day of addiction, when the patient was receiving 60 mg of NIH-7519 daily, a second nalorphine test was carried out, using a dose of 2 mg subcutaneously. Throughout the addiction period, and for 15 days after withdrawal of NIH-7519, observations for symptoms of abstinence were made three times daily. Daily point scores were calculated by the method of Kolb & Himmelsbach [ 9] .
Experiment 7. - "Long" Direct Addiction to NIH-7525
An experiment analogous to that employed in the above "long" NIH-7519 test was used for evaluating NIH-7525. The starting dose was 4 mg daily, with a comparable increase in dosage. It was planned to continue the chronic administration of NIH-7525 for 100 days, but after 26 days the subject requested that he be allowed to withdraw from the experiment, and no further drug was administered. A maximum dosage of 26 mg divided among four equal doses was attained on the 23rd day, and this was continued through the 26th day. Observations for intensity of abstinence [ 9] were made for ten days, beginning on the 27th day of the test. Precipitation of abstinence with nalorphine was not attempted.
Experiment 8. - " Short ", "Double-blind" Addiction Tests with Morphine and Placebo Controls
Eight patients served in these experiments, which were designed to determine whether a "short" direct addiction test could be used to assess the addictiveness of new drugs employing morphine and codeine as the standards for comparison. The patients received the following medications in randomized order for periods varying from 19 to 20 days: placebo (capsules of starch flavoured with quinine, orally); codeine sulfate in capsules, increasing from 200 mg to 1,500 mg daily; morphine sulfate in capsules, increasing from 40 to 240 mg daily; ethyl-4-phenyl-1 (3-cyano-3, 3-diphenylpropyl)-4-piperidine carboxylate HCl (R-1132) in capsules, increasing from 40 to 300-480 mg daily; d-3-methoxy-N-phenethylmorphinan in capsules, in doses increasing from 180 to 1,200 mg daily; morphine sulfate subcutaneously, increasing from 32 to 240 mg daily; NIH-7519 subcutaneously, increasing from 4.8 to 12-36 mg daily; and NIH-7525 subcutaneously, increasing from 4.8 to 24-36 mg daily. Only the data obtained with the placebo, morphine subcutaneously, NIH-7519 and NIH-7525 are pertinent to this report. The higher maximal dosages for NIH-7519 and NIH-7525 were those in the original design. These dosages, however, proved to be more than the first patients who received these amounts could safely tolerate, so the maxima were reduced to 24 mg daily in the case of NIH-7525. Unfortunately, all patients had completed addiction to NIH-7519 before this change in the dosage schedule was made. The identity of the drugs was known only to one person who prepared the solutions and capsules, and issued them in coded bottles. Drugs were withdrawn by substituting placebo capsules or injections appropriate to the drug being given. The person in charge of the drugs also decided on which day (19th-20th) drugs would be replaced by placebos. Withdrawal periods lasted ten days, after which the patient began another round of chronic drug administration.
Observations were made three times daily. These included rectal temperature, respiratory rate, pulse rate and blood pressure. Caloric intake was measured daily. Body weight was recorded at 6 a.m. daily. In addition, hours of sleep, hours of inactivity (lying horizontal on bed), initiative activity (hours off the ward) were recorded at half-hour intervals daily. Prior to starting the experimental regimen, control observations, including those mentioned above, were carried out for three days in order to accustom patients to all routines. Two complete blood counts and two urinalyses (including a test for bile) were made during this interval. Blood counts and urinalyses were made at intervals of three weeks thereafter.
Throughout the experiments, observations for symptoms of abstinence were made according to the procedures of Kolb & Himmelsbach [ 9] . Daily point-scores were calculated according to the method of the same authors, using the averages for respiratory rate, blood pressure, and temperature during the last seven days on the drugs (standard, Himmelsbach). In addition, other scores were calculated, using the means of the measurements during the period in which placebos were administered for 30 consecutive days (modified, Himmelsbach). The areas under the time-action curves for ten days of abstinence (TAS-10s) were calculated by the method of Winter & Flataker [ 15] for the respective drugs and methods of scoring. Differences in the TAS-10 scores between morphine, NIH-7519, and NIH-7525, and between all three drugs and placebo were scored by the "t" test for paired observations [ 5] . In this method of analysis, each patient served as his own control. The differences in the daily point scores obtained by both methods of scoring on the second and third days of abstinence were also evaluated by the "t" test for replicated data.
At 7 p.m. on each day of the experiment, each patient completed a questionnaire dealing with the subjective effects of the drug he was receiving, and concurrently a separate questionnaire dealing with the behavioural changes observed was completed by an aide. The method is being described in detail elsewhere [ 7] .
Experiment 1. - Effects of Single Doses Subcutaneously
The data on the subjective effects of morphine, NIH-7519 and NIH-7525 are presented in table 1.
TABLE 1
Subjective effects after morphine, NIH-7519 and NIH-7525
|
Drug
|
Dose (mg)
|
Number of study subjects
|
Number of patients responding a
|
||||
|
Positive opiates
|
Positive, other drugs
|
Questionable
|
Nega-tive
|
Average total responses b
|
|||
|
Placebo
|
-
|
16 | 0 | 0 | 0 | 16 | 0.4 |
|
Morphine
|
8 | 12 | 4 | [1] | 5 | 3 | 7.2 |
|
Morphine
|
13 | 17 | 12 | 0 | 4 | 1 | 15.4 |
|
Morphine
|
20 | 16 | 14 | 1[1] | 1 | 0 | 23.7 |
|
NIH-7525
|
2 | 17 | 12 | 0 | 4 | 1 | 15.4 |
|
NIH-7525
|
3 | 17 | 15 | 0 | 0 | 2 | 19.8 |
|
NIH-7519
|
3 | 17 | 10 | [1] | 4 | 3 | 12.0 |
|
NIH-7519
|
4 | 17 | 10 | 1 | 3 | 3 | 15.5 |
With respect to classification of the questionnaires as "positive for opiates ", it is apparent that the majority of the subjects regarded the subjective effects of doses of both NIH-7519 and NIH-7525 as being similar to those of morphine and heroin. Graded responses were obtained with the various doses of morphine and NIH-7525, but the response to NIH-7519 was flat, 10 of 17 patients responding "positively for opiates" on both doses. From the data, it seems that 2 mg of NIH-7525 and 3 mg of NIH-7519 are roughly equivalent to 13 mg of morphine. With respect to the total number of questions, graded responses were obtained with all three drugs. The dose-effect curves constructed from the mean number of positive responses are shown on the right side of figure 1. The relative potencies calculated from these curves with 95% confidence limits were: 1 mg of NIH-7519 equals 3.25 (2.32-4.25) mg of morphine, and 1 mg of NIH-7525 equals 6.11 (5.04-7.46) mg of morphine in inducing subjective effects. These curves met the usual tests for slope and parallelism. The dose-effect curves constructed from the means for total pupillary constriction appear on the left side of figure 1. The remarkable parallelism of these curves with those obtained with the total questions should be noted. The calculated relative potencies in constricting the pupil within 95% confidence limits were: 1 mg of NIH-7519 equals 3.81 (1.27-5.64) mg of morphine, and 1 mg of NIH-7525 equals 5.2 (2.74-7.95) mg of morphine. The agreement between the two estimates of potency for both NIH-7519 and NIH-7525, one derived from a subjective measurement (total responses on the questionnaire) and the other from an objective measurement, is rather astonishing. The lack of any significant response to placebo should also be noted. The time-course of action of the various doses of the three drugs was similar, and is shown in table 2.
FIGURE 1
Dose-effect relationship and relative potency for pupillary constriction and subjective responses with NIH-7525,
NIH-7519 and morphine. Single doses were administered subcutaneously to non-addicted, non-tolerant former addicts.
Comparative potencies of NIH-7519, NIH-7525, and morphine in constricting pupils and inducing subjective effects
TABLE 2
Average change from control in pupillary diameter in patients receiving morphine, NIH-7525 and NIH-7519
|
Drug
|
Dose (mg)
|
Number of study subjects
|
Hour after drug a
|
Total b "mm hours"
|
||||||||
|
Placebo
|
-
|
16 | 0.03 | 0.0 | 0.06 | 0.09 | 0.03 | 0.16 | 0.03 | 0.04 | 0.45 |
±0.17
|
|
Morphine
|
8 | 12 | 1.0 | 1.4 | 1.5 | 1.4 | 1.4 | 1.3 | 1.2 | 1.0 | 9.96 |
±1.28
|
|
Morphine
|
13 | 17 | 1.6 | 1.9 | 1.9 | 1.9 | 1.8 | 1.7 | 1.6 | 1.4 | 13.4 |
±1.35
|
|
Morphine
|
20 | 15 | 1.8 | 2.1 | 2.2 | 2.2 | 2.27 | 2.2 | 2.0 | 1.7 | 15.7 |
±2.0
|
|
NIH-7525
|
2 | 17 | 1.6 | 1.9 | 1.80 | 1.6 | 1.30 | 1.0 | 0.9 | 0.8 | 10.7 |
±1.4
|
|
NIH-7525
|
3 | 17 | 2.0 | 2.3 | 2.3 | 2.1 | 1.9 | 1.7 | 1.6 | 1.5 | 14.5 |
±1.55.
|
|
NIH-7519
|
3 | 17 | 1.3 | 1.5 | 1.6 | 1.4 | 1.3 | 1.1 | 1.1 | 0.8 | 9.7 |
±1.4
|
|
NIH-7519
|
4 | 17 | 1.7 | 2.1 | 2.2 | 2.0 | 1.8 | 1.6 | 1.7 | 1.5 | 13.8 |
±6.1
|
The behavioural changes observed after NIH-7519 and NIH-7525 were similar to those seen after morphine, and consisted of increased loquaciousness, increased psychomotor activity in some patients, sedation with alternating somnolence (" nodding ") in others, scratching, etc. These behavioural effects occurred even when subjective effects were denied.
TABLE 3
Single doses of NIH-7519 and NIH-7525 given intravenously (subjective identification and effects on pupillary diameter)
|
Number of subjects
|
Drug
|
Dose in mg
|
Identified as a
|
Maximum pupillary constriction (average, in mm)
|
Duration of pupillary constriction, in hours b
|
| 3 |
NIH-7519
|
2 |
1 placebo 1 morphine 1 heroin
|
2.4 | 4.5 |
| 5 |
NIH-7519
|
3 |
2 placebo 2 morphine 1 heroin
|
1.9 | 5.4 |
| 9 |
NIH-7519
|
5 |
1 placebo 1 morphine 7 heroin
|
2.8 | 6.3 |
| 7 |
NIH-7525
|
0.5 |
1 morphine 6 heroin
|
2.3 | 3.1 |
| 10 |
NIH-7525
|
1.0 |
1 morphine 1 dilaudid 8 heroin
|
3.00 | 6.5 |
| 4 |
NIH-7525
|
1.5 | 4 heroin | 3.5 | 7.0 |
Experiment 2. - Effect of Single Doses Intravenously
The data on the effects of NIH-7519 and NIH-7525 are shown in table 3. It is apparent that both compounds were identified consistently as either morphine or heroin; that the effect was quite intense, as indicated by the marked constriction of the pupil; and that it persisted for a considerable time, as shown by the duration of the pupillary constriction. Although no quantitative figure can be given, since not all of the subjects were used in both experiments, it is estimated that 1 mg of NIH-7525 is two to five times as potent as NIH-7519 when the drugs are given intravenously.
FIGURE 2
Dose-effect curves and relative potency for suppression of abstinence from morphine by NIH-7525 and graded doses of morphine. Twenty-four-hour substitutions in addicted individuals stabilized on 240 mg of morphine per day.
Experiment 3. - Suppression of Abstinence for 24 Hours
Both NIH-7519 and NIH-7525 proved to be potent suppressors of abstinence. The dose-effect curves constructed from the mean point-hour scores are compared with that of morphine in figures 2 and 3. The calculated potencies with 95% confidence limits relative to morphine for suppression of abstinence were: 1 mg of NIH-7519 equals 8.15 (4.23-17.25) mg of morphine and 1 mg of NIH-7525 equals 9.14 (4.78-19.5) mg of morphine. These estimates of potency are higher than those derived from the subjective response and pupillary constriction after single doses in non-tolerant subjects.
Experiment 4. - Substitution for Morphine for Ten Days
Both NIH-7519 and NIH-7525 were completely adequate substitutes for morphine. The daily point-scores during the last week of stabilization on 240 mg of morphine daily ranged between 0 and 8 points. After substitution of 32 mg of NIH-7519 daily, the daily point scores of the 2 patients fluctuated between 0 and 6 points, although one patient had scattered autonomic signs during the first two days of substitution. The point scores in the 3 patients who received 24 mg of NIH-7525 daily ranged between 0 and 7 during the ten days of substitution. Following discontinuation of both NIH-7525 and NIH-7519, definite morphine-like abstinence appeared. The symptoms included yawning, sweating, lacrimation, anorexia, insomnia, elevation of temperature, change in respiratory rate, weight loss, etc. The abstinence syndrome appeared somewhat more slowly than that of morphine, was less severe, and tended to be prolonged. The average TAS-7 score after withdrawal of morphine from patients stabilized on 240 mg daily would, from the data of Andrews & Himmelsbach (1), be expected to be 235 point-days. The TAS-7 scores after withdrawal of NIH-7519 from the 2 patients were 116 and 143. These scores correspond to those expected after withdrawal of morphine from patients stabilized on 55 and 78 mg of morphine daily. The TAS-7 scores after withdrawal of NIH-7525 were 164, 176, and 215. The scores correspond to those expected after withdrawal of morphine from patients stabilized on 99, 113 and 184 mg of morphine daily.
Experiment 5. - Preliminary "Short" Direct Addiction to NIH-7519 and NIH-7525
As the dosage of both these drugs was elevated, behaviour resembling that seen after chronic administration of morphine was observed in both patients and consisted of marked sedation, alternating somnolence and wakefulness (even while standing), vomiting, scratching, etc. The potency of the two drugs, when given chronically with initial rapid increase in dosage, was greater than that observed when the same patients had received morphine in doses increasing to 240 mg daily in 19 days or less in previous experiments. Obviously, the effects of NIH-7519 and NIH-7525 cumulate more than do those of morphine. Five mg of nalorphine precipitated definite symptoms of abstinence in both patients on the 16th (NIH-7519) and 17th (NIH-7525) days of addiction.
Following withdrawal of both drugs, both patients developed mild but definite morphine-like abstinence. The TAS-10 scores (total intensity of abstinence for ten days) were 125.0 after withdrawal of NIH-7519 and 54.0 after withdrawal of NIH-7525. The only data available after withdrawal of morphine after such a short period of addiction appears below in the section on short double-blind direct addiction (experiment 8). The TAS-10 values (scored from standard, Himmelsbach averages) in the 8 patients following withdrawal of morphine in that experiment ranged between 156.5 and 306.0. It should be pointed out that the patient who received NIH-7525 had consistently shown an abstinence syndrome of mild grade in previous studies when opiates were withdrawn abruptly. This is supported by the fact that 8 other patients who received NIH-7525 for a comparable time had TAS-10 scores ranging from 129.5 to 209.0 (see experiment 8).
FIGURE 3
Dose-effect curves and relative potency for suppression of abstinence from morphine by NIH-7519 and graded doses of morphine. Twenty-four-hour substitutions in addicted individuals stabilized on 740 mg of morphine per day.
Experiment 6. - "Long" Direct Addiction to NIH-7519
The patient who served in this experiment developed the same sort of subjective and behavioural changes described above. Mild but definite abstinence was observed after administration of 5 mg of nalorphine on the 18th day of the experiment, and moderate abstinence occurred after 2 mg of nalorphine on the 77th day of the experiment. This patient developed a high degree of tolerance to the drug, as manifested by nearly complete disappearance of the sedative effects before the end of the addiction period, despite the high dosage.
During the 42-hour withdrawal period, on the 24th to the 26th day, the patient did not realize that he was abstinent until 16 hours had elapsed since the last dose of NIH-7519. The abstinence syndrome was quite mild, and by the third day the patient seemed nearly recovered. Following withdrawal on the 127th day, the patient developed severe morphine-like abstinence phenomena, which appeared rather slowly and declined slowly. The maximum daily point score of 57 was not attained until the 4th day, and the patient still had a score of 29 points on the 15th day of abstinence. The symptoms included the usual autonomic phenomena as well as restlessness, anorexia, fever, hyperpnea, insomnia, and weight loss (15 lb in four days). The TAS-7 score was 304, and corresponds to that expected after withdrawal of morphine from a patient stabilized on 278 mg of morphine daily.
Experiment 7. - " Long" Direct Addiction to NIH-7525
The patient who served in this study developed the same type of subjective and behavioural changes described above in the preliminary trial. However, while his dosage was being progressively increased, he complained intermittently of "gas in the stomach ", nausea, and of being depressed about one hour prior to getting his injection. On the 26th day of chronic drug administration, when he had attained a dosage of 26 mg daily, the patient requested that he be taken off the test, complaining that the drug made him nervous and depressed, and saying, "I don't look forward to anything anymore, not even my next shot. I think about death or a severe illness in myself, such as cancer, or illness in my family." He concluded that if this were the only drug available to him, he would quit drugs entirely. The drug was discontinued abruptly and a moderately severe abstinence ensued.
This patient was called to the ward 20 days after having received his last injection of NIH-7525, and was given 1 mg of this drug intravenously, without knowledge of its identity. He stated it was like dilaudid, and was very pleased with the over-all effects.
Experiment 8. - " Short", "Double-blind" Direct Addiction
No difficulty was experienced in elevating the dosage of morphine or NIH-7525. All 8 patients attained a daily dosage of 240 mg of morphine by the 18th day of the experiment. The total amount of morphine taken by each patient during the test was 2,644 mg. Two patients who began on NIH-7525 prior to lowering of the maximum dosage to 24 mg daily attained a daily dosage of 36 mg, while 6 who began after the schedule was changed attained a daily dosage of 24 mg. The average total amount of NIH-7525 taken by the patients was 286.2 mg. Difficulty was encountered in elevating the dosage of NIH-7519. As explained in the section on methods, all patients completed this portion of the experiment before the maximum dosage was reduced from 36 to 24 mg daily. Only 3 of the 8 patients attained the full 36-mg dosage. The remaining 5 patients all developed symptoms of excessive drug effects - heavy sedation, nausea, and respiratory depression - so that their dosages were reduced or held at the same level for some days. Under these circumstances, the daily dosages of NIH-7519 attained by 5 patients varied between 12 to 26.4 mg daily, and the average total amount taken by the patients was 327.4 mg. The average daily dosage of NIH-7519 reached by all 8 patients was 25.95 mg daily. This is equivalent to approximately 210 mg of mor- phine daily in suppressing abstinence. The average daily dose of NIH-7525 attained by all 8 patients was 27 mg. This is equivalent to approximately 247 mg of morphine daily in suppressing abstinence. Throughout the experiment, all 8 patients consistently recognized that the subjective effects of NIH-7525 were similar to those of an opiate. Although all 8 patients reported at some time during the experiment that the subjective effects of NIH-7519 were similar to those of an opiate, as a group they were not as consistent respecting NIH-7519 as they were respecting NIH-7525. Four of the 8 patients identified the subjective effects of NIH-7519 as being opiate-like only occasionally.
The aides, however, consistently reported behavioural changes such as increased loquaciousness, alternating somnolence and sedation (" nodding" or "coasting "), and scratching, throughout administration of both NIH-7519 and NIH-7525. Such behavioural changes were also observed during administration of morphine.
The average effects of NIH-7519, NIH-7525 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 NIH-7519, NIH-7525 and morphine all depressed respiratory rate significantly. As compared with a placebo, none of them affected significantly systolic blood pressure, rectal temperature or hours of sleep per day. As compared with a placebo, morphine, NIH-7519 and NIH-7525 all depressed, but not to a statistically significant degree, initiative activity (i.e., hours which the patients spent off the ward), and increased the number of hours of inactivity (i.e., the number of hours the patients remained in bed). Hence, both NIH-7519 and NIH-7525 resembled morphine in their pattern of effects.
TABLE 4
Average effects of drugs as compared with a placebo on certain physiological measurements for all subjects during the first 18 days of medication
|
Drug
|
Respiratory rate
|
systolic blood pressure
|
Rectal temp., °C
|
Sleep in hours
|
Activity hours
|
Inactivity hours
|
|
Placeboa
|
18.8 | 109.7 | 37.03 | 7.08 | 3.34 | 10.35 |
|
Morphine
|
13.8b | 109.2 | 37.07 | 6.86 | 2.65 | 11.20 |
|
NIH-7519
|
14.8b | 106.1 | 37.10 | 7.10 | 3.03 | 11.89 |
|
NIH-7525
|
14.0b | 109.7 | 37.04 | 6.74 | 2.57 | 11.10 |
Both patients and aides promptly reported the appearance of symptoms of abstinence when the drugs were discontinued.
Intensity of abstinence as indicated by daily point-scores and TAS-10 scores are shown for morphine, NIH-7519 and NIH-7525 (fig. 4). These are compared with the intensity of abstinence which was observed when a placebo was considered to be the drug of addiction. Intensity of abstinence following withdrawal of NIH-7519 and NIH-7525 was significantly less than that observed following withdrawal of morphine, as shown by the TAS-10 scores of these drugs compared with morphine (P is less than 0.02 when the areas were compared using both the standard and the modified Himmelsbach methods). The differences at the peak were also highly significant on the second day of abstinence (P was less than 0.01). On the third day of abstinence, however, the difference between morphine and NIH-7525 was not significant when the modified scoring method was used.
FIGURE 4
Comparative intensity of abstinence after abrupt withdrawal of morphine, NIH-7519, NIH-7525 and placebo. As explained in the text, daily point-scores were computed both by using the averages for temperature, respiratory rate, etc., during the last seven days of addiction (standard Himmelsbach method), and also by using the averages during 30 days on placebo (modified Himmelsbach procedure). The TAS-10 values represent the mean areas (total intensity of abstinence for 10 days) plus or minus standard errors of the mean.
As compared with pre-drug values, chronic administration of medications did not provoke any significant alterations in white or red blood-cell counts, differential white-cell counts, hematocrit, sedimentation rates and urinalyses. There were no significant changes in body weight.
NIH-7519 has been found to be three to five times as potent as morphine as an analgesic in man [ 14] [ 10] [ 12] , and NIH-7525 is approximately twice as potent as NIH-7519 [ 13] . These values agree well with the figures on potency derived from pupillary constriction and euphorogenic qualities herein described.
Although Eckenhoff [ 4] and Prevoznik & Eckenhoff [ 12] have remarked on the paucity of side effects (including respiratory depression) with NIH-7519, respiratory depression during direct addiction experiments was just as great with NIH-7519 and NIH-7525 as it was with morphine.
One difference from morphine shared by both of these compounds is that the dosage of both, particularly NIH-7519, could not be increased proportionately as rapidly as that of morphine. When morphine was used in parallel addictive studies, it was always possible to increase the dosage from 40 mg daily to 180 to 345 mg daily (depending upon body weight) within the first 18 days of administration. In fact, it was possible to increase the dosage of morphine sulfate in non-tolerant former opiate addicts to 500 mg daily within ten days without the development of dangerous toxicity [ 6] .
The data show unequivocally that NIH-7519 and NIH-7525 are addictive materials in man. Both drugs are potent euphoriants, both are far more potent than morphine in suppressing symptoms of abstinence from that drug, and both are completely adequate substitutes for morphine. Both drugs created physical dependence resembling that caused by morphine in direct addiction experiments, and definite abstinence occurred after withdrawal of both drugs after substitution for morphine for ten days.
Physical dependence on both drugs may be milder than on morphine, or may develop more slowly. The TAS-7 and TAS-10 scores were consistently lower than those predicted for equivalent doses of morphine after short direct addiction experiments and after substitution for morphine. The severity of abstinence in the one patient who received NIH-7519 for 127 days shows that under conditions of abuse, abstinence from this drug can, in some persons at least, be as severe as abstinence from morphine.
The great discrepancy in the potencies of both NIH-7519 and NIH-7525 in suppressing abstinence from morphine in man as compared with their potencies in suppressing abstinence in monkeys [ 3] is of course evident. For example, in man, 1 mg of NIH-7519 equals 8.15 mg of morphine, but in the monkey, 1 mg of NIH-7519 equals 0.18 mg of morphine - a disparity of 45-fold in the two species. 6 The opposite type of quantitative discrepancy in the two species is also known to occur, since the monkey is relatively sensitive to members of the meperidine group, whereas man is relatively insensitive. These species differences are chiefly quantitative and not qualitative, since most drugs so far tested which suppress abstinence in man will also suppress it in the monkey, even though the dosages in the two species may vary greatly.
6 Dr. G. A. Deneau, of the Department of Pharmacology, University of Michigan, confirmed the chemical identity of the preparations used to estimate potency in monkeys and man.
The human pharmacology including addictiveness of dl-2'-Hydroxy-5,9-dimethyl-2(2-phenethyl)-6,7-benzmorphan HBr (NIH-7519) and l-3-Hydroxy-N-phenacylmorphinan methane sulfonate (NIH-7525) have been evaluated.
In single doses given by both the intravenous and subcutaneous routes, NIH-7519 and NIH-7525 are more potent than morphine in inducing subjective effects (euphoria), in provoking morphine-like behaviour, and in constricting the pupils.
Both NIH-7519 and NIH-7525 are potent suppressors of the morphine abstinence syndrome, and are completely adequate substitutes for morphine in addicted persons.
When the dosage of NIH-7519 and NIH-7525 was rapidly accelerated during chronic administration (addictive schedule), the over-all pattern, including side effects of both, was similar to that of morphine, except that it was not feasible to increase the dosage of NIH-7519 and NIH-7525 (especially the former) as rapidly as that of morphine.
Following withdrawal of NIH-7519 and NIH-7525, after substitution for morphine or after direct addiction, definite morphine-like abstinence phenomena appeared, which tended to be less severe than abstinence following withdrawal of equivalent amounts of morphine.
a For method of scoring, see text. Figures in brackets represent patients who also scored effects positively for opiates.
b These figures are the averages of the total number of positive responses over the eight-hour period described in the text.
a All figures represent mean change (decrease) in mm at the particular hour indicated.
b These figures are the means plus or minus standard errors of the area under the time-action curves.
00p000a Figures refer to the number of subjects. Designation of specific drugs by all subjects was very definite in these experiments when the drugs were administered intravenously (impressions of subjects are less well crystallized when drugs are given subcutaneously).
b Based upon the number of hours for pupils to return to within 1.0 mm of pre-drug status. Observations were extended to 8 hours after drug, and if pupils had not returned to within 1.0 mm of the pre-drug value by then, a value of 8.5 hours was used.
a Each patient was on a placebo for 30 consecutive days, but this tabulation covers only the first 20 days on placebo.
b Value is very significantly different from that observed when a placebo is given. The paired "t "value comparing morphine and a placebo is 11.18; comparing NIH-7519 and a placebo it is 11.86; and comparing NIH-7525 with a placebo it is 9.45.
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