Human pharmacology and addictiveness of certain dextroisomers of synthetic analgesics:

Sections

General methods
Detailed methods and results

Details

Author: H. F. Fraser, M.D.,, Harris Isbell, M.D.
Pages: 25 to 35
Creation Date: 1962/01/01

Human pharmacology and addictiveness of certain dextroisomers of synthetic analgesics:

I. d -3-hydroxy-N-phenethylmorphinan II. d -3-methoxy-N-phenethylmorphinan III. d -methadone

H. F. Fraser, M.D.,
Harris Isbell, M.D.
Of the National Institute of Mental Health, Addiction Research Center, U.S. Public Health Service, Lexington, Ky.

Introduction

Usually one of the optical isomers of synthetic analgesics (opioids) that possesses an asymmetric carbon atom accounts for most of the pharmacologic activity and the addictiveness of the racemic compound. The other isomer generally exhibits less activity and less addictiveness.

Methadone is an outstanding example of a compound in which greatly different activity and addictiveness occur in the optical isomers. /-methadone is a potent analgesic with addictiveness comparable to morphine [ 1] . d-methadone, in contrast, is a weak analgesic of low addictiveness. Isbell & Eisenman [ 2] observed no objective or subjective morphine-like effects after administration of 15-90 mg of d-methadone to non-tolerant former addicts, and no significant amelioration of abstinence from morphine when 30-90 mg of d-methadone were administered subcutaneously to addicted patients 32-36 hours after abrupt and complete withdrawal of morphine. In contrast, l-methadone was very potent in inducing morphine-like effects in non-tolerant patients and in suppressing abstinence from morphine. These authors concluded that l-methadone accounted for all the addictiveness of racemic methadone.

Recently, McCarthy et al. [ 3] found that d-methadone did reduce the intensity of abstinence in addicted monkeys, and estimated that 25 mg/kg was approximately equivalent to 3 mg/kg of morphine in suppressing abstinence. In view of the observations of McCarthy and co-workers, and the possibility of d-methadone being marketed for antitussive, antidiarrhoeal or other therapeutic usages, a re-evaluation of its addictiveness in man, using higher doses than those employed by Isbell & Eisenman, was necessary. In addition, studies on the addictiveness of the dextrorotatory isomers of 3-hydroxy-N-phenethylmorphinan and 3-methoxy-N-phenethyl-morphinan were thought to be of interest since both compounds, like d-methadone, had very low activities when compared with the l-isomers [ 4] .

General methods

The subjects used in these studies were healthy adult negro or white males serving sentences for violation of state or federal narcotic laws who volunteered for the experiment. All were former opiate addicts.

An effort was made to evaluate each of the three d-isomers in the maximal dosage that could be administered subcutaneously. The low solubility of these agents in water limited the amount that could be subcutaneously administered, and because of their low activity only minimal effects were observed when this route was employed. In addition, therefore, all drugs were administered orally in capsules over a considerable dosage range employing in so far as feasible the maximal safe dosage, and compared with morphine, codeine, and a placebo.

Usually each patient served as his own control in cross-over experiments, which were either double-blind (drug and amount unknown to subject and observer), or single-blind (drug and schedule unknown to subject).

Statistical comparisons between drugs, when the design permitted, were made by the paired t-test [ 5] , and relative potencies determined by the method of Bliss [ 6] . For convenience of presentation, the specific details of methods and results will be described for each experiment.

Procedures for preparation and the chemical properties of the compounds studied were as follows: d-3-hydroxy-N-phenethylmorphinan hydrobromide (I) was prepared by Drs. O. Schnider, A. Grussner & J. Hellerbach, of Hoffmann-La Roche, Inc., in Basle, Switzerland, as follows: d-3-hydroxymorphinan is prepared by the resolution of dl-1( p-hydroxybenzyl)-l, 2, 3, 4, 5, 6, 7, 8-octahydroisoquinoline with d-tartaric acid and benzylation, cyclization and debenzylation of the l-isomer to form d-3-hydroxy-N-methylmorphinan. This was treated with phenylethyl bromide to form (I). I is alkylated at 0 by means of phenyltrimethylammonium hydroxide to form the codeine analogue, d-3-methoxy-N-phenethylmorphinan (7296A). Purification steps for both compounds were repeated until no further change in the measurable physico-chemical criteria took place; this was attained at a residual contamination of less than 0.1%. d-methadone hydrochloride (340 g) was prepared through the courtesy of Dr. Earl H. Pierson, of the Merck Chemical Division, Merck & Company, Inc., Rahway, N. J., according to the method of Drs. Gene Howe & Max Tishler, U.S. patent 2,644,010, 30 June 1953.

This sample was combined with two other small samples (12 and 32 g) of d-methadone HCl, prepared by Burroughs Wellcome, and purified by Drs. R. Baltzly & J. Seed by two recrystallizations. The first crop (268 g) from the second recrystallization was the sample used in these studies. It had an optical rotation [ ? ]24.7/D = 129.3. The mother liquor was dried, and it gave an optical rotation of [ ? ]24.7/D = 124.2.

The maximum amount of impurity of the d-methadone HCl sample was calculated to be not greater than 0.3% of l- methadone. [ Note: The degree of impurity is probably less than this, and the sample used had a higher dextrorotatory activity than any reported in the literature to date.]

Detailed methods and results

PART I

d -3-hydroxy-N-phenethylmorphinan hydrobromide Effect of single subcutaneous or single oral doses in non-tolerant subjects

Methods. - This drug was evaluated in non-tolerant former opiate addicts. Pre-drug and seven post-drug observations were made at hourly intervals, and included measuring pupillary diameter and responses to a questionnaire, as described in detail by Fraser & Isbell [ 7] .

Results. - This compound was evaluated in nine tests in doses ranging from 2 to 20 mg subcutaneously. None of the subjects showed or reported any effects from these dosages. Because of the low solubility of the drug, higher doeses could not be evaluated by this route. Using 12 subjects in 17 trials, d-3-hydroxy-N-phenethylmorphinan hydrobromide was administered orally in a dose range of 20-300 mg, and no morphine-like effects were observed or reported. The only definite subjective effect experienced by any subject was a barbiturate-like sensation reported by one of 7 subjects who received 300 mg.

Twenty-four-hour substitution of d -3-hydroxy-N-phenethylmorphinan hydrobromide

Methods. - An average total dose of 1,040 mg of this compound (three equal oral doses) was substituted for morphine in 10 patients. All patients receiving morphine had been stabilized on 240 mg of morphine sulfate daily, administered subcutaneously in four 60-mg doses. During the 24-hour period of substitution, each patient received three doses of d-3-hydroxy-N-phenethylmorphinan instead of the three 60-mg doses of morphine. The study was controlled in other tests negatively by substitution of a placebo for morphine, and positively, by continuing the customary dose of morphine in the same subjects. Observations for intensity of abstinence were made hourly from the 11th through the 24th hour of abstinence [ 8] , [ 9] .

Results. - d-3-hydroxy-N-phenethylmorphinan was ineffective in suppressing abstinence (as measured by the Himmelbach hourly point scores), since the scores observed after this drug were practically identical with those observed after a placebo (figure 1).

Conclusion

In the dosages employed, d-3-hydroxy-N-phenethylmorphinan hydrobromide shows no evidence of an opiate-type of addictiveness.

PART II

d -3-methoxy-N-phenethylmorphinan tartrate (7296A)

Effect of single doses subcutaneously and orally of 7296A in nontolerant subjects

Methods. - These were the same as those used to ascertain the effect of single dose of d-3-hydroxy-N-phenethylmorphinan.

Results. - 7296A was evaluated in six tests in a dose range of 10-35 mg subcutaneously and, except for one subject who became drowsy, no effects were observed. Since the solubility of the drug was limited, it was not practicable to test higher doses subcutaneously.

Seven subjects received 70-150 mg, 10 subjects 200 mg, and 6 subjects 300 mg of 7296A orally. None showed or reported definite morphine-like effects, although 3 were drowsy. In another series of 20 trials, 12 subjects were given single oral dose as follows: 400 mg, 3 subjects; 500 mg, 3 subjects; 600 mg, 2 subjects; 700 mg, 6 subjects; and 800 mg, 6 subjects. In these tests, patients identified 7296A as being morphine-like in only three of the trials, and possibly morphine-like in one instance. Usually 7296A was reported to produce barbiturate-like effects. Although identified primarily as a barbiturate, none of the patients showed motor incoordination; the only behavioural effect observed was sedation. The pupils were moderately constricted, and this effect lasted from two to six hours.

Effects of 7296A as compared with morphine and a placebo on respiratory minute volume, respiratory rate, rectal temperature and pupillary diameter

Methods. - 7296A (300 mg) was given orally in a cross-over, single-blind test to 9 non-tolerant subjects, and the effects compared with those induced by a placebo, and by 20 mg/80 kg of morphine sulfate, both administered subcutaneously. Drug and placebo were administered to the same subjects in randomized order at weekly intervals. Two pre-drug and six post-drug observations were made at hourly intervals [ 10] while subjects were resting in bed in an air-conditioned, sound-proofed room. Measurements included rectal temperature, respiratory rate, respiratory minute volume, pupillary diameter, pulse rate, and blood pressure.

Results. - 7296A slightly, but non-significantly, decreased rectal temperature, respiratory rate and pupillary diameter as compared with a placebo, whereas morphine significantly decreased these measures. Blood pressure and pulse rate were not affected by any of the medications.

Twenty-four-hour substitution of 7296A for morphine

Methods. - Two experiments were done at different times. In the first, 6 patients who were addicted to 200-300 mg of morphine sulfate daily by the subcutaneous route (average 243 mg) received during the interval of substitution 1,000-1,200 mg (average 1,067) of 7296A orally. In the second experiment, 5 patients who were receiving 240 mg of morphine sulfate daily received 1,800 mg of 7296A (divided into four oral doses) in a 24 - hour period after discontinuation of morphine. Absti-nence scores from the eleventh through the twenty-fourth hour after the last dose of morphine were computed as described in part I.

FIGURE 1 Suppression of abstinence Shows the average intensity of absinence during 24-hour substitution of (i) d -methadone, (ii) 7296A and (iii) d -3-hydroxy-N-phenethylmorphinan for morpine in patients addicted to morphine, evaluated by the Himmelbach hourly point scores. Each drug is also compared with a placebo and with morphine continued in the usual dosage in the same individuals.

Full size image: 44 kB, FIGURE 1 Suppression of abstinence Shows the average intensity of absinence during 24-hour substitution of (i) d-methadone, (ii) 7296A and (iii) d-3-hydroxy-N-phenethylmorphinan for morpine in [...]

Data were available for comparison on 9 other patients, who received during 24-hour substitution tests 10% (18 mg), 20% (36 mg), and 50% (90 mg) of their accustomed dose of morphine. From these data, and the data on substitution of 7296A, regression line, estimate of potency as compared with morphine, and 95% confidence limits were calculated according to the methods described by Bliss [ 6] .

Results and discussion. - In these dosages, 7296A partially but incompletely suppressed symptoms of abstinence (figure 1). One mg of morphine was equivalent to 24.3 mg of 7296A, with 95% confidence limits of 6.78 to 57.6 mg. The highest dosage substituted was 1,800 mg, and is the maximum which could be employed safely in such a test, since the patients developed such evidence of toxicity as dizziness, anxiety and nervousness.

It should be pointed out that d-3-methoxy-N-phenethylmorphinan (7296A) was moderately active in substitution tests, yet it was prepared by methylation of the quite inactive d-3-hydroxy-N-phenethyhnorphinan compound. This difference in activity was in the opposite direction from that anticipated, since 7296A could be considered to be the "codeine" analogue and d-3-hydroxy-N-phenethylmorphinan the " morphine" analogue.

"Short", double-blind direct addiction tests with 7296A

Methods. - Eight patients served in this experiment which was designed to determine whether a " short ", direct addiction test could be used to assess the addictiveness of new drugs.

Seven drugs and a placebo were administered in randomized order for periods varying from 18 to 20 days. Drugs pertinent to evaluating the addictiveness of 7296A were administered orally in capsules as follows: placebos (starch flavoured with quinine); codeine sulfate, increasing from 200 to 1,500 mg daily; morphine sulfate, increasing from 40 to 240 mg daily; and d-3-methoxy-N-phenethylmorphinan (7296A), increasing from 180 to 1,200 mg daily. The identity of the drugs was known to only the person who prepared the capsules and issued them daily in envelopes identified only by the recipient's name. Drugs were abruptly withdrawn by substitution of identically appearing placebo capsules. The person in charge of drugs also decided on which day (19th or 20th) drugs would be replaced by placebos. Withdrawal periods lasted 10 days, after which the patient began another round of chronic drug administration.

Observations were made three times daily, and included rectal temperature, respiratory rate, pulse rate, and blood pressure. Caloric intake was measured daily and body weight recorded at 6 a.m. daily. In addition, hours of sleep, hours of inactivity (lying on the bed), and 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 and to obtain basal data. 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.

FIGURE 2 Summary of "subjective" ratings by patients (P), and "objective" ratings by aides (A ) These were tabulated from the responses of patients and aides to chronic dosage opiate questionnaires during the 18- to 20-day double blind cross-over study of addiction to morphine, codeine, 7296A and placebo, all orally administered.

Full size image: 72 kB, FIGURE 2 Summary of

Observations for symptoms of abstinence throughout the experiment were made according to the procedures of Kolb & Himmelsbach [ 11] , and daily point scores were calculated according to a method by these same authors, and as modified by Fraser & Isbell [ 7] . 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, separate questionnaires dealing with the behavioural changes observed were completed by the aides [ 12] .

Results. - All 8 patients completed this study. As compared with a placebo, morphine, codeine and 7296A significantly depressed the respiratory rate, but none of the other variables measured were affected significantly by any drug. The extent to which each of these drugs was detected, identified as dope (opiates), the estimate of strength (potency), and the positive attraction of the patients for the drug ("would like to take daily") as compared with a placebo, is illustrated in figure 2. Although patients (P) gave 7296A a low rating in all of these parameters, the aides (A) considered it as having some charac-teristics of an opiate and were impressed by its sedative qualities. The average maximal daily dose of 7296A attained was 1,200 mg. The oral dose of 7296A equivalent to 240 mg of morphine subcutaneously, based on 24-hour substitution tests, would be 5,830 mg [ 12] . This dose was not attainable because of the development of such undesirable effects as headache, dizziness, palpitation and nervousness. However, it should be pointed out that the equivalent substitution dosage of morphine orally [ 12] , as compared to morphine subcutaneously, was not attained (i.e., only 240 mg rather than 686 mg daily). Likewise, the equivalent dose of codeine was not attained (i.e., only 1,500 mg daily, instead of 3,530 mg).

FIGURE 3 Comparative intensity of abstinence after abrupt withdrawal of morphine, codeine, 7296A, and a placebo 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. The paired t -test was employed to compare statistically corresponding methods for estimating the degree of abstinence observed after withdrawal of each drug as compared to that observed after withdrawal of the placebo when the latter was considered to be the " drug of addiction " . One asterisk indicates P 0.05; two asterisks, P 0.001; and no symbol shows no significant difference.

Full size image: 34 kB, FIGURE 3 Comparative intensity of abstinence after abrupt withdrawal of morphine, codeine, 7296A, and a placebo Daily point scores were computed by using the averages for rectal temperature, re[...]

When 7296A was discontinued abruptly, all patients recognized that the medication had been changed, and initially there were scattered subjective sensations of "kicking a habit". However, none of the aides at any time observed signs of withdrawal, and the abstinence scores were statistically not significantly different from the scores after withdrawal of a placebo (figure 3). On the other hand, point scores indicative of physical dependence were observed after abrupt discontinuation of morphine and codeine (figure 3). In addition, abrupt withdrawal of morphine and codeine was associated with a temporary marked increase in hours of inactivity, which paralleled the intensity of abstinence scores, but this phenomenon did not develop after abrupt withdrawal of 7296A.

" Short " direct addiction (5 days) with 7296A, d-methadone and codeine, attempting to use doses which were consistently euphorogenic

Methods. - Since, in the case of drugs with low euphorogenic potency, 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 attempt to continue this dosage for five days. All of these drugs and a placebo were administered orally in identically appearing capsules in a randomized schedule. The daily dosage was as follows: 7296A, 2,000 mg; d-methadone, 900 mg; diphenoxylate, 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 diphenoxylate were given in only three equally divided doses rather than four. The sequential schedule was as follows: (i) 10 days of placebo; (ii) 5 days of one of the "active" drugs selected at random - i.e., 7296A, d-methadone, diphenoxylate or codeine; and (iii) 10 days of placebo followed by another "active" drug, etc. Thus, each "active" drug was preceded and followed by 10 days of placebo. Patients were unaware of the identity of drugs given or of the sequence of administration. They were advised that certain of the drugs might induce toxic symptoms, and that they could voluntarily discontinue medication at any time. All observers knew the complete schedule and were instructed to discontinue any drug and/or administer nalorphine promptly should any serious symptom of intoxication develop. Observations were made daily, as enumerated for the short (18-20 days) direct addiction test, including completion of "subjective" and " behavioural " questionnaires [ 12] .

Results. - The effects of the various drugs respecting certain parameters (excluding those of diphenoxylate which are not pertinent to this study) are illustrated in figure 4. Details of the effects of d-methadone are presented in part III.

Only 2 of 4 patients completed five days on 7296A. Medication had to be discontinued in one patient after two doses had been given on the second day because of nausea, severe abdominal cramps and complete anorexia. Another patient described 7296A as being like a combination of morphine and benzedrine ( dl-amphetamine). On the second day he complained of nervousness, said that he was scared, and that somebody had made a mistake and given him too much. He vomited after one dose. On the third day his symptoms persisted, and, in addition, confusion and loss of memory developed. On the fourth day the patient continued to be dazed and confused, but a neurological examination was negative except for small pupils (2 mm). Medication was discontinued because of these serious toxic symptoms. Another patient completed five days on the medication, but manifested progressive intoxication which included sedation, confusion, and loss of memory for certain events that occurred on the fourth and fifth days of intoxication. The fourth patient completed five days on 7296A without serious signs of intoxication. Although liking the medication initially, he subsequently developed a distaste for it, and at no time during the five days did he identify 7296A as dope.

FIGURE 4, Summary of questionnaires by 4 patients in a "short" (5-day) direct addiction test, when an attempt was made to administer a continuously " euphorogenic " daily dose of d -methadone (900 mg), 7296A (2000 mg), and codeine (480 mg). These are compared with the responses after a placebo, administered for 10 consecutive days to the same patients.

Full size image: 61 kB, FIGURE 4, Summary of questionnaires by 4 patients in a

Codeine was always identified as dope, and the incidence of non-narcotic symptoms was low (figure 4). "Non-narcotic symptoms" means the patient listed on his questionnaire that the drug being taken induced sensations like marihuana, cocaine, barbiturates, alcohol, amphetamines, or other. The placebo was identified as such except by one patient, who, on occasion, said it was like a weak dose of morphine. However, even this patient differentiated the effects of the placebo from those of an active drug, since he complained repeatedly that he had a bad "connexion" (source of drugs) while on the placebo.

When these drugs were withdrawn after five days and replaced by a placebo, no definite signs or symptoms of abstinence were observed.

Summary and conclusions

  1. d-3-methoxy-N-phenethylmorphinan (7296A) was evaluated for addictiveness in former opiate addicts. No morphine-like effects were induced or observed when 7296A was given subcutaneously in doses of 10-35 mg. Because of its low solubility, it was not possible to give higher doses by this route.

  2. Single doses of as much as 800 mg orally in non-tolerant subjects caused no definite morphine-like subjective effects.

  3. In high dosage (1,000-1,800 mg), 7296A partially suppressed symptoms of abstinence from morphine during 24-hour substitution tests. Toxic symptoms precluded substitution of doses higher than 1,800 mg.

  4. In the "short" direct addiction test lasting 18 to 20 days, the aides considered that 7296A produced opiate-like effects, but rated these as less than those of codeine. On the other hand, patients did not consider 7296A to be an opiate, and gave it a low rating as a desirable drug. When 7296A was discontinued abruptly after 18 to 20 days of chronic administration, no signs of physical dependence developed.

  5. When 7296A was administered for five successive days in a high dosage (2,000 mg daily), attempting to produce continuous euphoria, signs of toxicity (nausea, vomiting, nervousness, confusion and loss of memory) developed, and it was necessary to discontinue 7296A in 2 of the 4 subjects.

Conclusions. - The addictiveness of d-3-methoxy-N-phenethylmorphinan (7296A) is minimal, and is substantially less than that of codeine.

PART III

d- methadone hydrochloride

Effect of single subcutaneous doses of d-methadone

Methods. - In 11 trials, 10-100 mg of d-methadone were administered in a single dose subcutaneously and evaluated for morphine-like effects in non-tolerant subjects, as described above.

Results. - None of the patients showed or reported morphine-like effects from any of these doses. Doses of 50 to 100 mg were very irritating, and for this reason further medication by this route was abandoned.

Effect of single oral doses of d-methadone

Methods. - d-methadone was administered orally in capsules at 7.30 a.m. to patients fasting. The study was conducted single-blind, using methods described in part I. Seven patients (group A) received 200 mg of d-methadone, 12 received 300 mg (group B), and 6 received 400 mg (group C). A pre-drug observation was made, and comparable observations completed 1,2, 3, 4, 6, 8, 10,12 and 14 hours after ingestion of d-methadone.

Results. - In group A, 2 of 7 patients reported the effects of 200 mg of d-methadone were similar to those of an opiate; in group B, after 300 mg, 7 of 12 patients reported positively for opiates; and in group C, which consisted of less sensitive patients, 4 of 6 reported positively for opiates after 400 mg of d-methadone. All doses moderately constricted the pupils.

24-hour substitution of d-methadone for morphine

Methods. - In a preliminary experiment, using the methods described above, it was demonstrated that 650 mg of d-methadone, either orally or subcutaneously, partially but significantly suppressed abstinence from morphine in patients stabilized on 240 mg of morphine daily (figure 1). Since d-methadone appeared to be as effective orally as it was subcutaneously in suppressing symptoms of abstinence from morphine, two additional experiments using orally administered d-methadone were set up as follows: one, using 5 other subjects on a 750-mg dose (divided among five oral doses 4, 8, 14, 18 and 22 hours after the last dose of morphine), and another in which 5 subjects received a 400-mg dose (divided among three oral doses) daily. Nine of these 10 patients received on other occasions 10% (18 mg), 20% (36 mg), and 50% (90 mg) of their accustomed dose of morphine sulfate subcutaneously (divided into three equal doses). Although patients were stabilized on 240 mg of morphine sulfate daily during the substitution, they would have received only three injections of 60 mg, or a total of 180 mg. The data derived from the substitution of partial doses of morphine were used to construct a dose-effect curve with which the effects of the various dosages of d-methadone were compared, as outlined above for 7296A [ 6] .

Results. - From the dose-effect curves for substitution of morphine and d-methadone it was calculated that 1 mg of morphine subcutaneously was equivalent to 15.3 mg of d-methadone orally (95% confidence limits 10.1-26.9 mg) in reducing the intensity of abstinence. These dose-effect curves met the statistical requirements for significance of slope and parallelism.

Ten-day substitution of d-methadone for morphine followed by abrupt withdrawal of d-methadone

Methods. - Five patients, addicted to 240 mg of morphine sulfate subcutaneously daily for 118 to 178 days, had d-methadone substituted in an average daily dose of 520-730 mg orally (divided among three equal doses) for morphine for 10 days: then d-methadone was withdrawn abruptly and identically appearing placebo capsules substituted (figure 5). Observations for intensity of abstinence were made daily during both the period of d-methadone substitution and withdrawal [ 11] . For comparison, the intensity of abstinence from morphine observed by Kolb & Himmelsbach in 65 untreated cases is illustrated.

FIGURE 5 Substitution and withdrawal of d -methadone Average intensity of abstinence (daily point scores) in 5 patients under the following conditions: (i) while stabilized on 240 mg of morphine daily, (ii) when morphine was discontinued, and d -methadone substituted in an average daily dose of 520-730 mg, and (iii) when d -methadone was discontinued abruptly and replaced by a placebo. For comparison, the average intensity of abstinence observed in 65 cases addicted to morphine, abruptly withdrawn, and untreated (Kolb & Himmelsbach [ 11] ) is shown.

Full size image: 34 kB, FIGURE 5 Substitution and withdrawal of d -methadoneAverage intensity of abstinence (daily point scores) in 5 patients under the following conditions: (i) while stabilized on 240 mg of morphine[...]

Results. - In so far as the abstinence scores show (figure 5), d-methadone substituted quite effectively for morphine in these patients, since the maximal daily point score was only 14 during substitution. However, during substitution of d-methadone, all patients had a multiplicity of complaints, including nervousness, insomnia, nausea, vomiting, impaired vision, and frightening dreams. Because of such symptoms the patients voluntarily asked for a reduction in their dosage of d-methadone. When d-methadone was abruptly withdrawn after 10 days, a mild but definite abstinence syndrome developed. The maximal daily point score was 19 (figure 5).

Direct addiction to d -methadone

Methods.- The general plan was to compare the effects of successive administration of a placebo, dl-methadone, placebo, d-methadone, placebo, and d-methadone. The sequence of drugs, average individual doses, and the number of days on each regimen are illustrated in table 1. In addition, nalorphine (5 mg) was administered during the control period and again during chronic administration of d-methadone. The effect of these doses of nalorphine were compared with saline injections, also given during the control period and administration of d-methadone. Nalorphine and saline were given intramuscularly, but all other medication, including placebos, were prepared in identically appearing capsules and administered orally on a double-blind basis.

Observations were the same as those outlined for the direct addiction study of 7296A, except that tests for precipitation of abstinence with nalorphine were added, and observations for activity and inactivity were not included.

Results. - None of the patients identified the placebo as an opiate (dope), but all identified dl-methadone, in a relatively small dose, as a potent opiate and liked its effects (table 1). When dl-methadone was discontinued, residual effects persisted (table 1).

TABLE 1

Double-blind, direct addiction test with d -methadone a

Subject No.

Placebo

dl-methadone

Placebo

 
Days on
% dope (patients)
% opiates (aides)
Days on
Av. dose daily (mg)
% dope (patients)
% opiates (aides)
Days on
% dope (patients)
% opiates (aides)
1 8 0 0 3 47 67 67 7 14 14
2 9 0 0 5 45 100 100 10 10 10
3 7 0 0 3 20 100 100 12 8 75
4 8 0 0 2 47 100 50 13 8 23
5 32 0 3 4 48 75 100 20 5 50
Average
12.8 0 0.6 3.4 41.4 88.4 83.4 12.4 9.0 35.0

Subject No.

dl-methadone

Placebo

dl-methadone

 
Days on
Av. dose daily (mg) b
% dope (patients)
% opiates (aides)
Days on
% dope (patients)
% opiates (aides)
Days on
Av. dose daily (mg)
% dope (patients)
% opiates (aides)
1 20 650 0 0 10 0 0        
2 59 750 0 39 10 0 40        
3 62 873 0 60 10 0 10 2 375 0 0
4 62 802 2 73 10 0 0 2 325 0 0
5 58 650 5 86 10 0 0 2 500 0 0
Average
52.2 745.0 1.4 51.6 10.0 0 10.0 2 400 0 0

a Table illustrates the percentage of days the successive agents were classified as dope (" subjective" evaluation by patients) or as an opiate (" objective" evaluation of behaviour by aides). The regimen of each patient was continuous and sequential from left to right.

b This is average daily dose for each patient from the 18th day on d-methadone to the last day on this drug. (The initial daily dose, rate of increase, and maximum dosage of d-methadone attained in each patient is described in the text.)

During the prolonged interval of administration of d-methadone (20-60 days), patient No. 3 started with a daily dose of 200 mg, and the other four with a daily dose of 100 mg, but by the 10th day the former had attained a dose of 500 mg, the others 300 mg. All were receiving 650 mg daily on the 18th day. Patient No. 5 (table 1) displayed a progressive loss of weight, anorexia, some weakness, and nervousness, and for these reasons it was not possible to increase his dosage above 650 mg. Patient No. 2 attained a dose of 900 mg by the 28th day, and was maintained at this level. Patient No. 4 attained a dose of 1,000 mg on the 51st day. During chronic administration of d-methadone, all subjects showed a decrease in pupillary diameter, pulse rate, respiratory rate, systolic blood pressure and body weight (table 2). In addition, those taking d-methadone for 60 days developed a lymphocytosis and neutropenia. Physicians and aides were quite impressed with the opiate-like characteristics of d-methadone in 4 of the 5 subjects (table 1), and with the depression of physiological measurements in all patients, as shown in table 2. They frequently observed sedation. On the other hand, patients rarely reported that d-methadone was an opiate (see table 1). However, subjective effects were experienced by all patients; these included feelings of relaxation, occasional nausea, and anorexia. Some patients described an initial relaxed sensation, which was followed by one of nervousness. None liked the effects of d-methadone.

TABLE 2

Average effects of placebo, dl -methadone, and d -methadone a

Effect on

Placebo (pre-drug)

dl-methadone

d-methadone (week of addiction)

      1st 4th 6th 8th
Pupillary diameter (mm) (0) b
3.78 2.90 3.40 3.23 3.28 3.18
Respiratory rate/min. (3) b
16.5 13.5 14.8 13.0 13.0 13.3
Pulse rate/min. (3) b
64.0 61.0 56.3 54.3 56.6 58.5
Systolic blood pressure (3) b
111.5 112.3 106.5 107.5 107.5 109.5
Body weight, kg (3) b
71.64 71.38 71.08 69.17 68.26 67.80
a

Only the 4 subjects who were addicted to d-methadone for 60 days are included.However, observations on the other subject (No. 1) who was addicted for only 20 days are consistent with these.

b The figure in parentheses indicate the number of subjects out of a total of 4, in which the parameter referred to is significantly different statistically when the first interval, while receiving placebo, is compared with the long interval while receiving d-methadone (15th to 50th day). Each individual was compared with himself, and the data were not combined for this analysis.

Failure of patients to report morphine-like subjective effects in this test might be due to a more rapid tolerance to "euphoric" effects, as compared to the rate of development of tolerance to sedative and/or toxic effects (table 2). This may be the case, since when daily doses of 900 mg (comparable to the stabilization dose in this direct addiction test) were administered to non-tolerant subjects, opiate-like subjective effects developed. The failure to report opiate effects during the early portion of the direct addiction cycle can possibly be attributed to the "smallness" of the dose. The quality and intensity of the effects induced represent another variable [ 12] .

FIGURE 6 Withdrawal of d- methadone Average intensity of abstinence in 4 patients addicted to orally administered d -methadone for 60 days (lower left graph). For comparison, there is illustrated the average pattern and intensity of abstinence which developed after abrupt withdrawal or oral codeine (Fraser et al . [ 14] ), subcutaneous dl -methadone (Isbell et al . [ 13] ), and subcutaneous morphine (Himmelsbach [ 8] ).

Full size image: 31 kB, FIGURE 6 Withdrawal of d- methadoneAverage intensity of abstinence in 4 patients addicted to orally administered d-methadone for 60 days (lower left graph)

Patients Nos. 2, 3, 4 and 5, after 58, 55, 40 and 35 days respectively on d-methadone, received on alternate days either 5 mg of nalorphine or saline, and both agents were evaluated on a double-blind basis for ability to precipitate an abstinence syndrome. With the shorter interval of addiction (35 or 40 days) no signs of abstinence developed after nalorphine. Patient No. 2, after 58 days of addiction, although showing no definite objective signs, stated that "the room felt colder." Patient No. 3 showed mild but definite signs of abstinence (yawning, lacrimation, rhinorrhoea, perspiration, mydriasis, and elevation of rectal temperature). Saline injections (controls) produced no effect.

Intensity of abstinence when d-methadone was discontinued abruptly is compared with that manifested by abrupt withdrawal of codeine, dl-methadone and morphine in other experiments (figure 6). Only the data from the 4 subjects who received d-methadone for 60 days are included in figure 6. A mild but definite abstinence syndrome with a peak of 19 to 19.5 points [ 11] on the second and third days respectively developed after discontinuation of d-methadone, and symptoms gradually subsided over the next several days (figure 6). Patient No. 1, who was addicted to d-methadone for only 20 days, showed no overt signs of abstinence on withdrawal of the drug, but had a mild increase in his abstinence score.

"Short" direct addiction (5 days) with d -methadone; attempting to use doses which were consistently euphorogenic

Methods. - The methods employed are described in part II.

Results. - d-methadone in a dosage of 900 mg daily was consistently identified as an opiate, and induced a fairly typical pattern of morphine-like effects both subjectively and objectively. All patients complained of nervousness, and reported that an amphetamine-like (stimulant) action was superimposed on the sedative effect. One patient had hallucinations on the fourth day and refused further medication. Two patients, although consistently identifying d-methadone as an opiate, stated they did not like the subjective effects, and would not want to take it daily. Two patients, who liked the effects initially, changed their attitude as the experiment advanced - one going from a positive to an indifferent attitude, and the other going from a positive to a negative attitude, primarily because of complaints of nervousness, nausea, confusion, and mental depression.

Summary and conclusions

1. Single subcutaneous doses of d-methadone up to 100 mg induced no subjective or objective evidence of morphine-like effects in non-tolerant former opiate addicts. d-methadone is poorly soluble in water and a potent tissue irritant. For these reasons, higher doses were not feasible by this route.

2. Single oral doses of 200-400 mg of d-methadone consistently produced effects comparable to those of 20-30 mg of morphine orally or 60-90 mg of codeine orally in non-tolerant subjects.

3. d-methadone in the dosages employed partially suppressed abstinence from morphine in 24 - hour and 10-day substitution tests. One mg of morphine sulfate was estimated to be equivalent to 15.3 mg of d-methadone.

4. In direct oral addiction tests of 20 days in one subject, and 60 days in 4 subjects, the daily dosage of d-methadone was gradually increased from 100 or 200 mg the first day to 650 mg by the 18th day, and to 650-1,000 mg by the 60th day. It was not feasible to increase the dosage above the maximums indicated because of disturbing side effects. Although definite objective morphine-like effects were observed (sedation, miosis, depression of respiration, nausea, vomiting, and constipation), patients consistently denied that they experienced satisfying subjective opiate-like sensations, and on the whole they disliked the effect, whereas they liked those of dl-methadone, which was given to each patient for a few days for comparative purposes. After 35-40 days of addiction to d-methadone, 5 mg of nalorphine did not precipitate abstinence, but after 55-58 days one patient showed a definite moderate abstinence syndrome. The other patient showed no objective signs, but probably subjective changes were noted. After 20 days of addiction to d-methadone, no overt signs of abstinence were detected on withdrawal, but after 60 days, a definite but mild abstinence developed.

5. Administration of high dosages (euphorogenic) for five days, although initially liked by former addicts, became progressively less acceptable because of disturbing effects (nervousness, insomnia, nausea, vomiting, anorexia, disturbing dreams, and hallucinations).

Conclusions. - d-methadone, if given in adequate dosages, induces morphine-like subjective effects, partially suppresses abstinence from morphine, and creates a mild degree of physical dependence. Therefore, it has morphine-like addictive properties. The degree of addictiveness, as judged by these experiments, is less than that of codeine, because of its low solubility and tissue irritant properties, because a milder degree of physical dependence is induced (response to nalorphine and intensity of abstinence after direct addiction), and because dosages which are capable of inducing morphine-like euphoria also provoke undesirable effects on repeated administration.

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000

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010

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012

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013

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