Pharmacology and addiction liability of dl- and d-propoxyphene

Sections

INTRODUCTION
General Methods
DISCUSSION
SUMMARY AND CONCLUSIONS

Details

Author: H. F. Fraser,, Harris Isbell
Pages: 9 to 14
Creation Date: 1960/01/01

Pharmacology and addiction liability of dl - and d -propoxyphene

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

INTRODUCTION

Alpha dl-1,2-Diphenyl-4-dimethylamino-3-methyl-2-propionoxy-butane hydrochloride, hereafter designated propoxyphene, was synthesized by Pohland & Sullivan [ 1] . There are four stereoisomers, but only the alpha d isomer ( d-propoxyphene) had analgesic activity in animals [ 2] (2). In equal doses (32.5 or 65 mg), d-propoxyphene hydrochloride and codeine phosphate were equally effective in reducing the discomfort of chronically ill patients [ 3] . In another analgesic study, Gruber et al. [ 4] reported that 50 mg of propoxyphene hydrochloride is approximately equivalent to 32.5 nag of codeine phosphate or 325 mg of acetylsalicylic acid. In a cross-over experiment, Cass & Freder ck [ 5] compared a placebo, codeine (32, 65 and 130 mg), and comparable doses of d-propoxyphene for relief of pain in 70 ambulatory, chronically ill patients. Although both drugs were readily differentiated from a placebo, it was not possible to distinguish statistically between equivalent doses of codeine and d-propoxyphene; however, codeine in doses of 65 and 130 mg was quite consistently superior to comparable doses of d-propoxyphene. On the other hand, in the treatment of postpartum pain, Lasagna & De Kornfeld [ 6] were unable to demonstrate a statistically significant difference between d-propoxyphene (32 and 65 mg) and a placebo. Since propoxyphene is related structurally to isomethadone, and since the d-isomer (Darvon, Lilly) is being used clinically, it was thought desirable to investigate their pharmacology, and particularly their addiction liabilities in man.

General Methods

The subjects used in these studies were healthy adult white or negro males serving sentences for violation of state or federal narcotic laws, who volunteered for the experiments. dl- and d-propoxyphene* were administered as the hydrochloride, morphine as the sulfate, and nalorphine (N-allylnormorphine) as the hydrochloride.

The tests employed to evaluate the addiction liability of these drugs included the following procedures: (i) administration of single doses for the detection of morphine-like (euphomgenic) effects; (ii) substitution of these drugs for morphine in patients addicted to morphine, to ascertain their effectiveness in preventing symptoms of abstinence from morphine (substitutions were for 24 hours and 14 days); (iii) "direct addiction ", which involves administration of these drugs in progressively increasing doses as tolerated for 18 days, stabilization on maximum dosage attained for an additional 28 to 36 days, and, finally, abrupt withdrawal of the drug to ascertain the presence and degree of physical dependence; and (iv) precipitation of abstinence by administration of 10 mg of nalorphine subcutaneously after 30 to 40 days of chronic intoxication with propoxyphene. Specific details will be described under each experiment.

We are indebted to Drs. Brown, Robbins and Gruber, Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana, for supplies of propoxyphene (Lilly 16298) and d-propoxyphene (Lilly 21720).

Part. I. Propoxyphene

Effect of single oral doses in non-addicted patients

The compound was administered orally in single doses in forty-one trials to 25 non-tolerant former addicts, the doses ranging between 50 and 1,000 mg. In thirteen trials with doses of less than 600 mg, no definite subjective or objective effects were recorded. With doses of 600 to 800 mg, patients became drowsy, and most of them reported dizziness. None of the patients stated that the effects were similar to those of morphine, until 800 mg were given, when 3 out of 8 subjects described the effects as resembling those of some kind of opiate. Four of the remaining patients were unable to identify the subjective effects, and one described it as being like barbiturates. One patient, who received 1,000 mg, had severe toxic effects (apprehension, nervousness, tremor, moderate pallor, and perspiration), which predominated over sedative effects.

The effects of a single dose of 600 mg on rectal temperature, pulse and respiratory rates, blood pressure, respiratory minute

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FIGURE 1. - Average effects (8 subjects) of 800 mg of propoxyphene orally on pupillary diameter and respiratory minute volume

The average of two pre-drug observations are shown at time zero. The degree of pupillary constriction observed approximates that seen after 20 mg of morphine sulfate given subcutaneously. A single dose of 800 mg of propoxyphene did not significantly depress respiratory minute volume.

volume, and pupillary diameter were determined in 8 subjects ( [ 7] , 8). The only significant change in any measurement was a decrease in pupillary size. Figure 1 illustrates observations on respiratory minute volume and miosis.

Twenty-four-hour substitution of propoxyphene for morphine in patients addicted to morphine

Eleven subjects who had been stabilized on 240 to 280 mg of morphine daily were given a total dose of 1,200 mg of propoxyphene during the first 24 hours after abrupt withdrawal of morphine. The drug was administered orally in doses of 200 mg at intervals of four hours, except at night, when the interval was six hours. In a similar study, using the same patients, the dose was increased to a total of 2,400 mg, given in divided doses of 400 mg each. In a control experiment, using a comparable schedule, the same subjects were given placebo capsules resembling the propoxyphene capsules. In a positive control experiment, 9 of these 11 subjects were given injections of morphine every four hours, and were informed only that another compound was being tested. The results of this experiment, using the 400-mg dose of propoxyphene (2,400 mg in 24 hours), are illustrated in figure 2. Intensity of abstinence was measured by the hourly point-scoring system [ 9] , beginning at the 14th hour of abstinence, and continuing at hourly intervals through the 24th hour. The

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FIGURE 2. - Substitution of propoxyphene for morphine for 24 hours

The figure compares the intensity of abstinence when propoxyphene was substituted orally for morphine with that observed when a placebo was substituted, and with that observed when the regular dose of morphine was continued. Each point on the placebo and propoxyphene curves represents the average scores of the same 11 subjects. Each point on the morphine curve represents the average score of 9 of these 11 subjects. The letter P signifies that the point is significantly different from the corresponding point for the placebo; M signifies that the point as significantly different from the corresponding point for morphine, indicating some suppressive effect on abstinence from morphine.

t-test for paired observations [ 10] was used in statistical analysis of data. When morphine was given, the hourly score fluctuated between 3 to 8 points. When placebo injections were substituted for morphine, the intensity of abstinence rose to 32 points at the end of the 24 hours. When propoxyphene was administered in doses of 400 mg every four hours, the intensity of abstinence was significantly reduced, beginning at the 14th hour and continuing through the 24th hour. Two of 9 subjects who received this dosage showed excessive sedation and depressed and periodic respiration, making it necessary to reduce two of the doses to 200 mg for one patient, and one dose for the other patient. Although all the other patients who received this high dosage showed diminished respiratory rate, the depression did not become sufficiently serious to warrant a reduction in dosage. With the 200-mg dose (total 1,200 mg) average intensity of abstinence from the 14th through the 24th hour was as follows: 14, 13, 14, 15, 16, 16 17, 18, 20, 20, and 23 hourly points. These scores are quite similar to those obtained with the 400-mg dose. With the smaller dose, no serious depression of respiration occurred, but definite sedative effects were present.

Direct addiction and precipitation of abstinence with nalorphine

Five healthy negro males who were former opiate addicts served as subjects. Propoxyphene was administered orally in capsules, and the total daily dose was distributed in three approximately equal doses. The dose was increased as rapidly as practical during the first 18 days of drug administration. Physical dependence was evaluated by abruptly withdrawing

TABLE 1

Drugs and dosages in different periods of the experiment *

Phase of experiment

Days

1. Progressive elevation of dosage of morphine sulfate until a dosage of 280 mg/80 kg per day was attained
18
2. Stabilization on 280 mg/80 kg of morphine
31
3. Substitution of codeine phosphate (1,600 mg/80 kg per day) in 5 subjects, or d-propoxyphene (800 mg/80 kg) in 5 subjects
14**
4. Placebo capsules, all 10 subjects
10 ***
5. Readdiction of all 10 subjects by progressive elevation of dose of morphine sulfate until a dose of 280 mg/80 kg was attained
18
6. Stabilization on 280 mg/80 kg of morphine
31
7. Substitution of codeine phosphate (1,600 mg/80 kg per day) in 5 subjects, or d-propoxyphene (800 mg/80 kg) in 5 subjects
14
8. Placebo capsules, all 10 subjects 10
10
  146

Morphine was given subcutaneously in four equal doses daily. Codeine, d-propoxyphene, and placebo were administered orally in identical capsules three times daily. The dosage in each capsule was adjusted so that the same number of capsules were given in the case of codeine, d-propoxyphene and placebo. The first dose of either codeine or d-propoxyphene was administered concurrently with the last dose of morphine at 6 a.m.

Order of substitution of codeine or d-propoxyphene was randomized among patients, and was continued for a variable number of days (13, 14 or 15), so that neither subjects nor observers could anticipate the exact day when the transition to placebo capsules was to be made.

On either the 9th or 10th day, all subjects who had continued to take placebos were given instead either one dose of codeine, if they had been receiving codeine; or one dose of d-propoxyphene, if they had been receiving d-propoxyphene.

propoxyphene after 46 days of addiction, and measuring the intensity of abstinence by the daily point-score system [ 11] . Physical dependence was also measured by administration of 10 mg of nalorphine subcutaneously after 30 to 40 days of addiction, and observing the degree of abstinence induced [ 12] This procedure was controlled in each subject by the random administration of a placebo instead of nalorphine. Toxicity was evaluated by clinical observations, and by the following laboratory tests which were performed prior to drug administration, and repeated during the fifth and sixth weeks of addiction: routine analyses, red and white blood cell counts, hemoglobin content, hematocrit, and liver-function tests (thymol turbidity and evidence of bilirubin in the urine).

The results of the direct addiction test were as follows: One subject withdrew from the experiment after six days, complaining of nervousness, and that medicine was like LSD ( d-lysergic acid diethylamide), vomiting and loss of 2.2 kg. Another quit after ten days, complaining that "the medicine makes me nervous; I can't sleep; I'm dizzy, and I'm losing weight" (1.3 kg). In all subjects a maximum dose of 1,200 mg daily was attained. However, it was necessary to reduce this dose to 850, 650 and 700 mg daily in the 3 subjects who continued the test for 46 days. The 3 subjects who completed the test were persuaded to do so by agreement that the dose which provoked significantly disagreeable symptoms would not be given. It should be stated that if a drug induces morphine-like effects, our subjects rarely discontinue a test, and instead of stipulating a minimum dosage to be administered, they request repeatedly that the dosage be increased. Drowsiness was observed repeatedly, and resembled that induced by an opiate, in that they could be readily aroused, but the patients did not consider the subjective effects comparable to morphine-induced "nodding". Nalorphine (10 mg) precipitated no signs of abstinence, and when propoxyphene was discontinued abruptly, the average scores [ 11] for the first seven days were 3, 4, 3, 5, 4, 4, and 3. The outstanding observations of the direct addiction experiment were: (i) the compound was disliked by all subjects because of its disagreeable effects (nausea, vomiting, constipation, production of nervousness and dizziness), and because it did not induce morphine-like euphoria; (ii) the compound produced little, if any, physical dependence as shown by the very low abstinence scores after abrupt discontinuation of propoxyphene, and the fact that 10 mg of nalorphine did not provoke signs of abstinence when given after 30 to 40 days of chronic drug administration; and (iii) no evidence of damage to kidneys, liver, or bone marrow was observed in the laboratory tests.

Part II. d-propoxyphene

The methods employed and the results obtained in part II ( d-propoxyphene) were very similar to those presented in part I (propoxyphene). Differences will be pointed out when they occur.

Effects of single oral doses in non-addicted patients

The compound was administered as an elixir in doses ranging from 50 to 650 mg. Twenty-three trials were made in 9 sub jects. In doses of 50 to 300 mg, effects were minimal, and there was no consistent pattern of response. With doses of 355 to 650 mg, patients liked the subjective effects, and related them to the effects of marihuana, heroin, morphine, and cocaine. With doses of 650 mg, nausea, vomiting and sedation were consistently present, and respiratory minute volume was depressed from 20 to 30% in all patients. Respiratory and pulse rates, rectal temperature, and blood pressure were not affected. (It should be pointed out that a dose of 650 mg is approximately ten times the maximum recommended analgesic dose.)

Effects of single doses subcutaneously in non-addicted patients

In five trials, doses of 5 to 60 mg caused no detectable effects. Two subjects given 120 mg reported that they might have received a small dose of morphine, and both complained of soreness at the site of injection. Of 4 subjects given 250 mg, 3 could not identify the effect, and one said it was like a small dose of heroin; 3 showed some miosis; none displayed characteristic morphine-like behavior; and all complained of sore arms.

Twenty-four-hour substitution of d-propoxyphene for morphine in patients addicted to morphine

Morphine was abruptly withdrawn from 8 subjects who had been stabilized on 240 to 280 mg of morphine daily. At 0, 6, 14 and 20 hours after the last dose of morphine, 200 mg of d-propoxyphene were given orally. The intensity of abstinence was reduced significantly, and to the same degree as by propoxyphene (figure 2).

Comparison of a fourteen-day substitution of d-propoxyphene for morphine with that of a fourteen-day substitution of codeine for morphine

The purpose of this study was to compare the addiction sustaining capacity of d-propoxyphene with that of codeine phosphate in patients physically dependent on morphine. The Kolb & Himmelsbach (11) daily point-score was used to measure intensity of abstinence. Behaviour of the patients during each substitution was carefully observed, and patients were questioned about the subjective effects of the drugs. Five negro and 5 white healthy male post-addicts volunteered for the study. The over-all plan of the experiment, drugs, and dosages is shown in table 2 and figure 3. The "double-blind" technique was followed, except that all subjects and observers knew that patients were addicted to morphine. Patients were told the drugs to be substituted for morphine had been previously tested at Lexington, but were given no other information. Codeine phosphate, d-propoxyphene, and placebos were all administered in identical capsules. The experimental plan was a cross-over design - each subject served as his own control for comparing the addiction-sustaining characteristics of codeine and d-propoxyphene. Both d-propoxyphene and codeine were substituted in a randomized order for 13, 14, or 15 days, then discontinued abruptly, and identical placebo capsules administered. The t-test for paired observations was used in statistical analysis of data [ 10] .

TABLE 2

Daily dose of d -propoxyphene substituted for 400 mg of morphine

 

Day

Subject

1

2

3

4

5

6

7

8

9

10

11

L. O.
1 200 1 200 1 200 1 200 1 200 300 300 400 100 200 200
H. A.
1 200 1 200 1 200 1 200 1 100 500 400 400 300 700 500
C. O.
1 200 1 200 900 900 900 900 900 900 600 300 300

Codeine suppressed abstinence from morphine very well, since the average daily point-score after substitution was more than 10 only on the second day (figure 3). When a placebo was substituted for codeine, there was a prompt rise in the intensity of abstinence to an average of 34 points on the third day of substitution, followed by a decline to 20 points by the eighth day (figure 3).

After substitution of d-propoxyphene for morphine, the intensity of abstinence rose promptly to 32 points on the second day, but was not as great as would have been anticipated had placebo been given instead of d-propoxyphene. This is illustrated by comparison of the intensity of abstinence observed when d-propoxyphene was substituted for morphine with that observed in the 65 untreated cases of Himmels- bach [ 9] (9). Codeine, however, was much more effective than d-propoxyphene in substituting for morphine (figure 3). When placebos were substituted for d-propoxyphene, there was no significant change in the abstinence scores (figure 3). For comparative purposes, when placebo capsules replaced codeine, there was a prompt and marked rise in the abstinence scores. (It hould be no ed that daily abstinence scores, when computed by the method of Kolb & Himmelsbach (11), continued at a relatively high level even after ten days. This is due in part to the persistence of actual symptoms of abstinence, and partly to an artefact in the scores, which arises principally from recovery of respiratory rate and blood pressure to normal levels from the subnormal levels observed during addiction [ 13] . The artefact arises because the baseline

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FIGURE 3. - Substitution of codeine and d-propoxyphene for 10 days

The figure illustrates (i) the over-all plan of the study and (ii) the intensity of abstinence during various phases, as evidenced by daily point-scores. The data from all 10 subjects have been averaged, and all are represented as having had codeine substituted for morphine first, and subsequently, d-propoxyphene substituted for morphine; whereas in the actual design, only 5 of the subjects had this sequence table 1). The letter P indicates that this point on the curve for substitution of codeine is significantly different from the intensity of abstinence observed at a corresponding point when d-propoxyphene was substituted for morphine.

for computing the scores is obtained from observations made during the last 7 to 14 days on the drug, rather than during a drug-free period.)

Patients consistently recognized codeine as a drug in the opiate category, whereas none classified d-propoxyphene as an opiate; the majority considered d-propoxyphene to be a sedative.

Toxic psychosis associated with an attempt to completely suppress morphine abstinence by substitution of d -propoxyphene in a high dosage

Morphine was withdrawn abruptly from 3 patients who had been stabilized on 400 mg of morphine sulfate daily, and a high dosage (table 2) of orally administered d-propoxyphene was substituted for the morphine for eleven days, after which the propoxyphene was abruptly discontinued. Intensity of abstinence was measured during the eleven days of substitution, and the first seven days after d-propoxyphene was discontinued. The average point-scores observed during substitution of this high dosage of d-propoxyphene were greater than those observed when 800 mg/kg of d-propoxyphene was substituted for 280 mg/kg of morphine.

On the evening of the fifth day that patient L. O. received 1,200 mg of d-propoxyphene daily he became extremely agitated, and an emergency call was made for his doctor. He recognized the physi ian, but approached him on his hands and knees, praying loudly and excitedly. He begged to be taken off medication and discharged from the ward. Interspersed with prayers asking to be forgiven, he recited in a very disconnected way the mistakes of his adult life. He started writing in a frantic manner, and continued in an agitated state all night. Concurrently with the reduction in dosage of d-propoxyphene, he improved progressively, and there were no sequelae. Another patient, H. A., was suspected of hallucinating when he was observed peeping out of doors into the corridor, without any particular reason. When questioned the next day, he admitted that at intervals he had been seeing and hearing imaginary people. A third patient, C. O., became nervous and apprehensive, but did not hallucinate, quite possibly because his dosage was reduced to 900 mg on the third day.

In another study using one subject, the intensity of abstinence from morphine was reduced by substituting methadone for a daily dosage of 250 mg of morphine, and then gradually reducing the dosage of methadone. On the third day of this reduction, the patient received 30 mg of methadone and 300 mg of d-propoxyphene, and on the fourth day, 20 mg of methadone and 900 mg of d-propoxyphene. Abstinence was very satisfactorily suppressed on the fourth day, but that night the patient experienced disturbing hallucinations which promptly receded when the dosage of d-propoxyphene was reduced to 300 mg daily.

The above studies, substituting very high dosages of d-propoxyphene, were concurrently controlled by substituting only methadone, which was orally administered in a progressively declining dosage to 2 other patients who were addicted to 400 mg of morphine daily. On this regime, abstinence was very effectively suppressed, and no psychotic behaviour developed.

The massive dosages which provoked psychoses in these patients are probably of the order of magnitude which addicts might attempt to use in trying to suppress symptoms of abstinence from opiates. They are from five to ten times greater than the recommended therapeutic doses.

Direct addiction and precipitation of abstinence with nalorphine

These were conducted on 5 healthy negro males. In general, the same plan was followed as that described for direct addiction to propoxyphene, except addiction was continued for 53 or 54 days, and laboratory tests were made at weekly intervals.

Dosages of d-propoxyphene larger than 800 mg daily may cause severe nausea, marked respiratory depression and even a toxic psychosis. Therefore, dosages significantly greater than this should not be given. This was thought especially advisable, since the degree of tolerance which developed to the toxic effects of the racemic form was much less than that observed for the opiates.

All subjects completed the test. For the first two or three days, all subjects liked the drug, and related the effects to those of morphine, heroin or marihuana, and their behaviour in most respects resembled that of patients given some type of opiate. But subsequently they began to complain - for example, saying: "It doesn't give me the right kind of high," "It makes me too drowsy," or "I'm constipated since starting medication." One patient lost weight slowly but steadily, complained of nausea, and vomited at intervals. It was necessary to reduce his daily dosage from 750 to 600 mg. The other 4 subjects attained a daily dosage of 825 mg, and continued on that level throughout the experiment. At the conclusion of the direct addiction study, the over-all attitude of each subject toward the drug was ascertained: one disliked the effects, 3 were indifferent, and one subject stated, "I think I would go for that medicine; it gives you a relaxed feeling like heroin, but I would rather have heroin." None of the laboratory tests conducted at weekly intervals showed any significant differences from pre-addiction observations.

Following 10 mg of nalorphine, 2 of the 5 subjects showed abstinence signs of slight degree. None of the subjects showed any effects following a placebo injection. (For comparative purposes, it should be stated that if this dose of nalorphine was given to patients addicted to 100 mg or more of morphine for 28 days, a very intense abstinence syndrome would be provoked.)

When d-propoxyphene was discontinued after 53 or 54 days of addiction, all of the subjects had subjective complaints (weakness, aching, sensations of heat and cold), and showed objective signs of abstinence, which were largely confined to the mildest category (yawning, lacrimation, rhinorrhea, and perspiration). The average daily point-scores of these 5 subjects during the first seven days of withdrawal of d-propoxyphene were 13, 14, 8, 8, and 7 points. By contrast, average scores following withdrawal of codeine in 16 cases reported by Himmelsbach et al. [ 14] for the first five days were much higher (11, 33, 30, 20, and 14 points)

DISCUSSION

These observations indicate by every criterion used - potency in inducing subjective effects resembling those after administration of morphine, ability to suppress symptoms of abstinence from morphine when evaluated in 24-hour an 14-day substitution tests, behaviour during addiction tests, intensity of abstinence following withdrawal, and degree of abstinence precipitated by nalorphine - that the addiction liabilities of both propoxyphene and d-propoxyphene are substantially less than that of codeine.

SUMMARY AND CONCLUSIONS

  1. Administration of single doses of propoxyphene (50 to 1000 mg orally) or of d-propoxyphene (50 to 650 mg orally or 5 to 60 mg subcutaneously) did not induce a full pattern of morphine-like subjective effects or behavioural changes.

  2. Sedation, miosis, depression of respiratory minute volume, nausea, and vomiting were observed with the higher doses of both drugs.

  3. When substituted for morphine for 24 hours in addicted patients, both propoxyphene (1,200-2,400 mg orally daily) and d-propoxyphene (800 mg daily) partially suppressed symptoms of abstinence from morphine.

  4. When substituted for morphine for 14 days, d-propoxyphene partially suppressed abstinence, but was much less effective than codeine. Following withdrawal of d-propoxyphene, there was no significant change in the intensity of abstinence, whereas after withdrawal of codeine, intensity of abstinence increased very significantly.

  5. Attempts to suppress completely abstinence from morphine with high dosages of d-propoxyphene (900 to 1,200 mg daily) were associated with a severe toxic psychosis that was readily reversed by a reduction in dosage.

  6. Two of 5 patients who received propoxyphene chronically withdrew from the experiment; 3 patients continued after the daily dosage was reduced from 1,200 to 700-850 mg daily; patients disliked the drug because of disagreeable side effects; 10 mg of nalorphine did not precipitate definite abstinence; following withdrawal of propoxyphene, only minimal abstinence was observed.

  7. In 5 patients d-propoxyphene was administered chronically in high dosage (600-825 mg daily) for 53 days. Early in this experiment, subjective effects and behaviour partially resembling those seen after morphine were observed; these rapidly subsided. After withdrawal of d-propoxyphene, only minimal symptoms of abstinence were observed.

  8. The addiction liabilities of propoxyphene and d-propoxyphene are substantially less than that of codeine.

References

001

POHLAND, A. & SULLIVAN, H. R., J. Am. Chem. Soc ., 1953, 75: 4458.

002

ROBBINS, E. B., J. Am. Pharm. Assn ., 1955, 44: 497.

003

GRUBEK, C. M., Jr., J. A. M. A ., 1957, 164: 966.

004

GRUBER, C. M., Jr., KING, E. P., BEST, M. M., SCHIEVE, J. F., ELKUS, F. & ZMOLEK, E. J . Arch. Internat. Pharmacodyn ., 1955, 104: 156.

005

CASS, L. J. & FREDERICK, W. S., Bull. Drug Addiction and Narcotics , 1959, appendix G, p. 2004 (unpublished).

006

LASAGNA, L. & DE KORNFELD, T.J., Bull. Drug Addiction and Narcotics , 1958, appendix C, p. 1783 (unpublished).

007

ISBELL, H. & FRASER, H. F., J. Pharm. and Exper. Therap ., 1953, 107: 524.

008

FRASER, H. F., NASH, T. L., VAN HORN, G. D. & ISBELL, H ., Arch. Internat. de pharmacodyn. et de therap. , 1954, 98: 443.

009

HIMMELSBACH, C. K., J. Pharm. and Exper. Therap ., 1939, 67: 239.

010

EDWARDS, A. L., Statistical Methods for the Behavioral Sciences , New York City, Rinehart, 1954.

011

KOLB, L. & HIMMELSBACH, C. K., Am. J. Psychiat ., 1938, 94: 759.

012

FRASER, H. F., WIKLER, A., VAN HORN, G. D., EISENMAN, A.J. & ISBELL, H., J. Pharmacol. and Exper. Therap ., 1957, 122: 359.

013

FRASER, H. F. & ISBELL, H.: Unpublished.

014

HIMMELSBACH, C. K., ANDREWS, H. L., FELIX, R. H., OBERST, F. W. & DAVENPORT, L. F., Pub. Health Rep., Supp. 158 . Washington, D.C., U.S. Govt. Ptg. Off., 940.