LABORATORY EVALUATION
CLINICAL EVALUATION
Author: Nathan B. Eddy
Pages: 39 to 44
Creation Date: 1953/01/01
Heroin is "a drug with no legitimate use. Its importation, manufacture or possession is illegal. It is four to six times more powerful than morphine. No drug is more habit-forming; none has more deleterious effects." Thus did a Washington Post article on January 4, 1953, describe the drug; such seems to be the opinion generally held in the United States. Is it justified by laboratory and clinical experience?
In the monograph, The Pharmacology of the Opium Alkaloids, by Krueger, Eddy and Sumwalt1 a chapter is devoted to heroin and a very extensive bibliography, including many references to clinical experience, is appended. No useful purpose would be served by reviewing again all of the older literature; more desirable would seem to be a summary of the laboratory data on the more important aspects of the drug's action with emphasis on quantitative comparisons with morphine.
The monograph stated that "heroin is strongly narcotic and analgesic for most animals." Eddy and Howes2reported that the analgesic dose of heroin in the cat was 0.43 mg./kg. intramuscularly, comparable to 0.75 mg./kg. of morphine, and that both drugs produced excitement in the cat in slightly smaller dose (0.4 mg./kg. for heroin, 0.53 mg./kg. for morphine). Seevers and Pfeiffer3found that heroin was analgesic, sedative, and sometimes euphoric for man (normal volunteers) at a dose of 2 mg. total subcutaneously or intravenously, and that its action was more rapid in onset but of shorter duration than that of morphine. The euphoric effect of heroin exceeded that of morphine. Lasagna and Beecher4 also gave heroin subcutaneously to a group of normal subjects in a total dose of 2 mg. Two of nine had slightly pleasant reactions, succeeded in one by an unpleasant depressed feeling. One subject considered his reaction definitely unpleasant. The chief complaint among the others was "fogginess'' and difficulty in concentrating, neither pleasant nor unpleasant. Morphine, 10 mg. subcutaneously, in the same subjects, also produced predominantly a feeling of grogginess and sleepiness with jittery feelings in some instances. To only one subject was the reaction definitely pleasant; he felt relaxed, peaceful, contented and optimistic. One other subject experienced definite physical and mental relaxation with a desire merely to sit back and enjoy the relaxation.
Thorp5 in 1946 re-assessed the analgesic effectiveness of heroin using a thermal stimulus applied to the tail of the rat. He found that 0.5 mg./kg. subcutaneously was slightly less effective than 3.5 mg./kg. of morphine and had a definitely shorter duration of action. Jackson,6also using a heat stimulus differently applied to the rat's tail and injecting the drugs intravenously, reported that for equal intensity of analgesic action 0.04 mg./kg. of heroin was equivalent to 2.0 mg./kg. of morphine, but that for equal duration of action the doses were 0.11 mg./kg. of heroin and 2.2 mg./kg. of morphine.
Still more recently, Herr, Nyiri and Venulet7 reported that heroin was 8.3 times more effective than morphine when administered subcutaneously to normal rats. They compared heroin with a 4.0 mg./kg. dose of morphine, an amount which was "100 percent analgesic"; that is, increased the reaction time (tail flick response to a radiant heat stimulus) in each of a group of 10 animals to more than 2.5 times the normal reaction time of the same group. The analgesic effectiveness of heroin and of morphine was reduced in rats in which the spinal cord was transected in the dorsal region. The reduction was proportionately the same for both drugs; the 100 percent analgesic dose was 20 mg./kg. for morphine, and heroin was 7.9 times more effective than morphine in the spinal animal. This result can be taken to mean that both drugs have the same sites of action for analgesic effect, according to the authors, all sites of transmission of nociceptive stimulation, in the cord, in the thalamus, and in the cortex.
In our experience,8 using a method of heat stimulation in mice,9comparable analgesic doses were 0.9 and 2.0 mg./kg. subcutaneously, and 15 to 20 and 3.9 mg./kg. orally, for heroin and morphine, respectively. The duration of action of heroin was barely half that of morphine. It is remarkable that, although heroin is more than twice as effective as morphine subcutaneously, morphine is 4 to 5 times more effective than heroin orally. The decrease in effectiveness of heroin when given orally, since heroin becomes less effective than morphine, can hardly be accounted for by prompt deacetylation. These results are on an experimental animal but they may make more understandable the large oral doses of heroin, 5 to 10 mg. and above, reported in the older clinical literature.
Dreser10claimed very early that heroin had a specific effect on the inspiratory phase of respiration, increasing its duration. He said that this would cause air to be drawn more deeply into the lungs and could be helpful in respiratory disease. A specific effect was not confirmed by other careful investigators; rather they have shown11 ,12 ,13 that heroin and morphine act qualitatively alike on respiratory activity, decreasing the rate, affecting variably tidal volume and decreasing significantly minute volume. Quantitatively, however, the difference is very sharp. For example, according to Impens140.42 mg./kg. of heroin subcutaneously had as much effect on the rabbit's respiratory minute volume as 1.5 mg./kg. of morphine. Wright and Barbour13said that the least dose causing a decrease in respiratory activity of the unanesthetized rabbit was 0.017 to 0.035 mg./kg. of diacetylmorphine and 0.32 mg./kg. of morphine administered subcutaneously. Larger doses, 0.25 mg./kg. of heroin or 2 to 3 mg./kg. of morphine, were required to lower the rabbit's rectal temperature or slow the heart rate. Keil and Pohls15reported that comparable doses for 40 to 50 percent reduction in respiratory minute volume were 0.225 and 2.8 mg./kg. for heroin and morphine, respectively. According to the last authors heroin was 12.5 times more potent as a respiratory depressant, 8 times more potent as an analgesic.
The older statements in the literature give little basis for a quantitative comparison of the effect of heroin on gastro-intestinal motility but indicate a qualitative similarity to morphine. Plant and Miller,16as the result of a very careful study of the action of morphine, said that it and heroin were approximately equal in potency, each increasing the tone of the intestine of the unanesthetized dog at a dose of 0.1 mg./kg., subcutaneously, or intramuscularly. Dreyer17indicated that heroin was twice as effective as morphine in modifying intestinal movements; but Walton18agreed with Plant and Miller on the quantitative similarity in the effect of heroin and morphine on the dog's intestine. In contrast to these observations, Eddy and Howes2 observed suppression of intestinal evacuation in the rabbit with 0.7 mg./kg. of heroin and 6.0 mg./kg. or morphine. Emesis occurred less frequently with heroin than with morphine in dogs16and cats.2
Heroin is more toxic and more convulsant than morphine in various animal species. Eddy and Howes2recorded an average fatal dose of 262 mg./kg. and a minimal convulsant dose of 196 mg./kg., subcutaneously administered in mice. The average fatal dose for morphine was 531 mg./kg. and convulsions very rarely occurred with survival. However, for morphine and its derivatives relative toxicity for animals is not a safe criterion of probable toxicity for man. A much better basis for prediction is the degree of respiratory depression produced in an unanesthetized animal because of the very great sensitivity to opiates of man's respiratory mechanism. Heroin is at least 10 times more potent than morphine as a respiratory depressant and consequently is likely to be at least 10 times more toxic for man. Compared to this probable 10:1 toxicity ratio the greater analgesic potency of heroin is not as impressive as it first appeared. The toxicity figures are for subcutaneous injection and the quantitative data for analgesic effect by the same route of administration rate heroin as only 2 to 8 times more effective than morphine. Also all agree that the duration of action of heroin is shorter.
It is perhaps not surprising that quantitative data on the effectiveness of heroin against cough are mainly lacking, since only recently have methods been developed for the production of cough in even an approximately reproducible manner. Hillis,19using a single human subject and spraying irritant vapors into the larynx, compared morphine ? grain, heroin 1/ 6 grain, methadone ? grain, codeine 1 grain and a placebo (normal saline), all given subcutaneously. All of the doses seem excessive but the author said that heroin was most effective and that codeine was no more effective than the placebo. The percent of trials with which drowsiness occurred was 86 for heroin, 68 for morphine, 69 for methadone and 43 for codeine. Beecher20was unable to suppress cough produced in normal human subjects by intravenous injection of small doses of paraldehyde. He tried 2.5 mg. of heroin subcutaneously, 10 mg. of codeine orally, 30 mg. of codeine intravenously and 5 mg. of morphine subcutaneously. This work is continuing with production of cough by a more "natural" method, inhalation of an irritant vapor, and extensive exploration of the usual, oral, route for antitussive medication.
Again referring to the monograph1the statement is made that, "Tolerance to at least some of its (heroin) effects have been seen in all of the animals studied." Two outstanding experiments have been carried out on the production of tolerance and addiction to heroin in monkeys with parallel observations on morphine. The one was by Kolb and DuMez,21and the other by Seevers.22The former made monkeys tolerant to heroin and morphine by daily subcutaneous administration. Doses attained in 8 to 10 months were 40 mg. of heroin (12 to 13 mg./kg.) and 180 to 200 mg. of morphine (75 to 90 mg./kg.) compared to starting doses of 2 to 4 mg. of heroin and 7 to 8 mg. of morphine. The dosage increment was greater for morphine than for heroin, but because of the difference in duration of action heroin was given several times a day toward the end of the experiment, morphine never more than twice. General deterioration in health occurred, worse with morphine, and severe abstinence symptoms upon abrupt withdrawal, again worse with morphine. In previously untreated animals 7 mg. of heroin or 85 mg. of morphine might kill but the average fatal dose was not determined. Depression, manifested by drowsiness, sleep and muscular weakness, occurred sooner and was of shorter duration but was more persistent in its occurrence immediately after an injection, throughout the experiment with heroin. After surviving a single large toxic dose of either drug, animals were a little less sensitive to another dose; but after prolonged daily administration and 6 weeks to 2 months of abstinence, sensitivity to either drug was greater than at the beginning of the experiment.
Seevers also found that depression was more rapid in onset and of shorter duration in the monkey with heroin than with morphine. In animals receiving the drugs subcutaneously daily for 9 months or more the morphine dosage was increased from 10 to 125 mg./kg., the heroin dosage from 2 to 25 mg./kg. Abrupt withdrawal was followed by equally severe abstinence phenomena with either drug; the signs of abstinence appeared earlier with heroin.
Two types of experiment on the addiction liability of heroin have been performed at the U. S. Public Health Service Hospital for addicts at Lexington, Kentucky. In the first experiment23heroin was substituted for morphine in 9 morphine addicts. These men had been stabilized on 140-400 (average 200) mg. of morphine daily. Heroin substituted for morphine in doses ranging from 40-120 (average 71) mg. daily, or a substitution ratio of 1 mg. of heroin hydrochloride for each 3 mg. of the stabilization dose of morphine sulfate. The heroin was subsequently abruptly withdrawn and the intensity of the abstinence syndrome which followed was measured by the method of Kolb and Himmelsbach.24The intensity of the abstinence syndrome has been plotted in fig. 1 on the basis of hourly point scores and in fig. 2 on the basis of total daily point scores. Average figures for a large group of morphine withdrawals are plotted on each graph for comparison. The significant difference is in the rapidity of onset and subsidence of the abstinence phenomena. The plotted curve for heroin crosses the 10-point level within 5 hours and the 15-point level within 7 hours. The plotted curve for morphine does not reach the 10-point level until the 13th hour and the 15-point level until the 15th hour. Also at the 39th hour the heroin abstinence intensity is already beginning to decline while that for morphine is still rising. The difference is not as striking in the daily point scores but again the curve for average intensity of heroin abstinence phenomena rises more rapidly, reaches a slightly higher level and subsides more rapidly than the corresponding curve for morphine.
Fig. 1. Intensity of abstinence syndrome in man, hourly point score, method of Kolb and Himmelsbach.24
- - Morphine
Ο- - Ο Heroin
Fig. 2. Intensity of abstinence syndrome in man, daily point score, method of Kolb and Himmelsbach.24
- - Morphine
Ο- - Ο Heroin
The second experiment25consisted in a direct addiction study on two former addicts, free of drugs and non-tolerant when the experiment was started. The experiment was designed for a different purpose and was not ideal for a direct comparison with morphine but nevertheless confirms and extends the results of the substitution study. Both subjects received heroin subcutaneously four times a day, 15 mg./dose from 3-30-52 to 4-25-52, 30 mg./dose from 4-26-52 to 5-9-52 and 45 mg./dose from 5-10-52 to 5-20-52. Morning pre-injection abstinence phenomena (yawning, lacrimation, rhinorrhea, mydriasis) were observed as early as 4-4-52, the 6th day on the 15 mg. dose, 5-2-52, the 7th day on the 30 mg. dose and 5-14-52, the 4th day on the 45 mg. dose. Once pre-injection abstinence phenomena began, they increased in intensity until the dose was raised and concomitantly the subjects demanded such dose increase. Each time the dose was raised the pre-injection phenomena disappeared temporarily but reappeared as indicated.
After 59 days of addiction, abrupt withdrawal of the heroin was followed by very severe abstinence symptoms, reaching peak intensity from the 19th to the 28th hour and largely subsiding by the 48th hour. After completion of the experiment the subjects were not asked if they preferred heroin but both were eager to start another heroin experiment.
On the basis of above and previous experience Dr. Wikler drew the following conclusions: Milligram for milligram heroin is more potent than morphine in the production of "satisfaction" for the addict; its action is more rapid, hence produces a greater sense of wellbeing; the duration of action is less and pre-injection abstinence phenomena appear sooner, hence, more frequent injections and more rapid increase in dose are inevitable; the intensity of the heroin abstinence syndrome is as great or greater than that of morphine and the peak is reached sooner, hence the over-all "need" for it is greater. There is evidence that being dependent (physiologically and psychologically) on opiate drugs is attractive to the addict for various reasons new direct sources of gratification, social esteem (successful "hustling," comparable to earning money, etc.) and also predisposition to relapse by making conditioning of pharmacological dependence possible. Finally, heroin is likely to be more addicting than morphine, conditions of a non-pharmacological nature being equal.
Heroin was introduced into clinical medicine in 1898 and there followed a flood of reports on its potency for pain and Cough particularly, minimizing the incidence of side effects and the possibility of addiction.
(See (1) for partial bibliography of clinical reports.) It is interesting to note, however, that one of the earliest clinical papers gave the clue to its potential danger and sounded a note of caution. Strube26reported that he had given heroin in doses of 5 and 10 mg. orally to 50 patients suffering from various respiratory disorders. He noted that there were no unpleasant subjective reactions; indeed the patients liked it and continued to take the heroin pills after he ceased to prescribe or had changed them to codeine for some reason. He admitted that this might indicate the possibility of addiction.
Heroin is a potent analgesic, perhaps 3 to 5 times more potent than morphine in man, though a controlled quantitative study of dose-effect relationship against pathological pain has not been done. It is also a powerful respiratory depressant in man, perhaps 10 times more powerful than morphine, though again a controlled quantitative study of dose-effect relationship, especially of the response to equally effective analgesic doses, has not been done. The most insistent claim for its continued use, however, stems from a supposed specific effect on cough.
The dose of heroin for oral administration commonly recommended in the literature ranges up to 10 mg. This does not suggest striking or specific antitussive action if one recalls that the oral antitussive dose of codeine need not be greater than 10 mg.27and that it is 5-10 mg. for dihydrocodeinone.28 ,29 The addiction liability of codeine is generally accepted as relatively low and that of dihydrocodeinone lies between the liability of codeine and morphine.30
At present we do not know that marked analgesic action or ability to depress respiration is essential for antitussive action. Evidence is accumulating for animals31,32and for man33that substances devoid of significant analgesic or other morphine-like action can relieve cough. Inasmuch as these substances with demonstrable antitussive but no analgesic action have also been shown to have no addiction liability 34 ,35 their development is most important and their clinical establishment should remove the last objection to the abandonment of heroin as a tool of legitimate medicine.
The claim of fewer side actions with heroin, particularly nausea and constipation, has persisted to the present time. It is based solely on clinical impression which, however, because of its mass must be given some weight. A carefully controlled study has never been carried out on normal subjects, free of the disturbing influence of a pathological condition, using morphine and a placebo for comparison, and administering the drugs as unknowns in equally effective analgesic doses. Such studies have been carried out for some of the new synthetic analgesics36and would seem to be the best means for quantitative estimation of side effects. Seevers and Pfeiffer3met partially the conditions just outlined, but their objective was not primarily assessment of side effects and they did not establish conclusively equally effective analgesic doses. They reported for their 8 normal subjects a lower incidence of side effects and a higher frequency of pleasurable reactions when doses of 1 and 2 mg. of heroin subcutaneously were compared with doses of 8 and 10 mg. of morphine.
Any feeling about the incidence of side effects with the use of heroin is overshadowed and far outweighed by its addiction liability. On this score there can be now no question. (The monograph1already referred to gives many references on this point.[*] ) Whether or not it is more liable than morphine to lead to tolerance and dependence in legitimate medical practice, it is the drug of choice in the illicit drug traffic and among a great many of the addicts which that traffic supplies, in part at least because of the small size of the effective dose, making for easier smuggling of profitable amounts, and the rapid and intense reaction which the addict experiences when the drug is given intravenously.
In conclusion one must say that any superiority for heroin has not been established by controlled quantitative data. Qualitatively it is like morphine. Any useful effects of heroin can be obtained with morphine and other morphine derivatives, some of which are certainly safer.29 ,30 ,37Besides we now have synthetic analgesics, methadone,38 ,39 ,40 l-isomethadone41 ,42 ,43 and 3-hydroxy-N-methylmorphinan [†] 44 ,45 ,46which can substitute for morphine pharmacologically. Heroin admittedly is subject to a high degree of abuse. If its deletion from the physician's armamentarium will aid in the fight against the illicit drug traffic, medical practice cannot suffer from its loss.
n001See also Kaffl-Lenz, Erich ("Causes of the chronic abuse of Narcotic Drugs," Bull. Narcotics, 4, 1, 1952) for a brief summary of the rise in production and abuse of heroin.
n002†Dromoran, methorphinan, or racemorphan.
Krueger, Hugo, Eddy, Nathan B. and Sumwalt, Margaret,
"The pharmacology of the opium alkaloids," U. S. Government Printing Office, Washington, 1943, Suppl. No. 165 to the Public Health Reports.
Eddy, Nathan B. and Howes, Homer A., "Studies of morphine, codeine and their derivatives. VIII. Monoacetyl and diacetylmorphine and their hydrogenated derivatives," J. Pharmacol. & Exper. Therap., 53, 430, 1935.
Seevers, Maurice H. and Pfeiffer, Carl C., "A study of the analgesia, subjective depression and euphoria produced by morphine, heroine, dilaudid and codeine in the normal human subject," J. Pharmacol. & Exper. Therap., 56, 166, 1936.
Lasagna, Louis and Beecher, Henry K., "Euphoria: A study of drug induced mood changes in man," Report to the Committee on Drug Addiction and Narcotics of the National Research Council, Jan. 9, 1953, unpublished.
Thorp, Roland H., "The assessment of analgesic activity in new synthetic drugs," Brit. J. Pharmacol. & Chemoth., 1, 113, 1946.
Jackson, Harold, " The evaluation of analgesic potency of drugs using thermal stimulation in the rat," Brit. J. Pharmacol. & Chemoth., 7, 196, 1952.
Herr, F., Nyiri, M. and Venulet, J. "Studies on the mode of analgesic action of morphine and morphine derivatives," Acta Physiol. Acad. Scientiarum Hungaricae, 3, 199, 1952.
Eddy, Nathan B. and Leimbach, Dorothy, Unpublished results.
Eddy, Nathan B. and Leimbach, Dorothy, "Synthetic analgesics II. Dithienylbutenyl- and dithienylbutylamines," J. Pharmacol. & Exp. Therap., In press.
Dreser, H., "Uber die Wirkung einiger Derivate des Morphins auf die Athmung," Arch. f.d. ges. Physiol., 72, 485, 1898.
Fraenkel, Albert, "Ueber Morphinderivate in ihrer Bedeutung als Hustenmittel," Münch. med. Wchschr., 46, 1527, 1899.
v. Issekutz, B., "Ueber die Wirkung des Morphins, Codeins, Dionins und Heroins auf die Atmung," Arch. f.d. ges. Physiol., 142, 255, 1911.
Wright, Charles I. and Barbour, Fleming A., "The respiratory effects of morphine, codeine and related substances. IV. The effect of alpha-monoacetylmorphine, monoacetyldihydromorphine, diacetylmorphine (heroin) and diacetyldihydromorphine on the respiratory activity of the rabbit," J. Pharmacol. & Exper. Therap., 54, 25, 1935.
Impens, E., "über die Wirkung des Morphins and einiger seiner Abkömmlinge auf die Athmung," Arch. f.d. ges. Physiol., 78, 527, 1899.
Keil, Werner and Pohls, "über Analgesie und Atemwirkung der Morphingruppe," Arch. f. exp. Path. u. Pharmakol., 181, 285, 1936.
Plant, O. H. and Miller, G. H., "Effects of morphine and some other opium alkaloids on the muscular activity of the alimentary canal. I. Action on the small intestine in unanesthetized dogs and man," J. Pharmacol. & Exper. Therap., 27, 361, 1926.
Dreyer, N. B., "Some effects of morphine and other opium alkaloids on intestinal motility of different animals," Arch. internat. Pharmacodyn. et Therap., 45, 397, 1933.
Walton, Robert P., "Absorption of drugs through the oral mucosa. II," Proc. Soc. Exp. Biol. & Med ., 32, 148, 1935.
Hillis, B. R., "The assessment of cough-suppressing drugs," Lancet. 1, 1230, 1952.
Beecher, Henry K., "A study of experimental and pathological cough," Report to the Committee on Drug Addiction and Narcotics of the National Research Council, Jan. 9, 1953, unpublished.
Kolb, Lawrence and DuMez, A. G., "Experimental addiction of animals to opiates," Pub. Health Rep., 46, 698, 1931.
Seevers, Maurice H., "Addiction potentialities of morphine, codeine, heroine, and dilaudid in the monkey," J. Pharmacol. & Exper. Therap., 51, 141, 1934; 56, 157, 1936.
Himmelsbach, C. K. and Isbell, Harris, Unpublished results.
Kolb, Lawrence and Himmelsbach, C. K., "Clinical studies of drug addiction. III. A critical review of the withdrawal treatments with method of evaluating abstinence syndromes," Am. J. Psychiat., 94, 759, 1938; Pub. Health Rep. Suppl. 128, 1938.
Wikler, Abraham, Personal communication.
Strube, Georg, "Mittheilung über therapeutische Versuche mit Heroin," Berlin. klin. Wchschr., 35, 993, 1898.
Davenport, Lowry F., "Studies of morphine, codeine and their derivatives. XIII. A clinical study of comparative effects of dihydroisocodeine and codeine," J. Pharmacol. & Exper. Therap., 64, 236, 1938.
Stein, P. and Lowy, P., "Hycodan: Dihydrocodeinone," Am. Rev. Tuberc., 53, 345, 1946.
Bonyai, Andrew L., "Management of cough in daily practice," J. Am. Med. Ass., 148, 501, 1952.
Fraser, H. F. and Isbell, H., "Addiction liabilities of morphinan, 6-methyldihydromorphine and dihydrocodeinone," J. Pharmacol. & Exper. Therap., 100, 128, 1950.
Benson, W. M., Stefko, P. L. and Randall, L. O., "Comparative pharmacology of d-, dl- and l-dromoran and related ether derivatives," Fed. Proc., 11, 322, 1952.
Winter, Charles A. and Flataker, Lars, "Antitussive action of d-isomethadone and d-methadone," Proc. Soc. Exp. Biol. & Med., 81, 463, 1952.
Cass, Leo J. and Frederik, Willem S., "Evaluation of antitussive agents: Clinical aspects." Report to the Committee on Drug Addiction and Narcotics of the National Research Council, Jan. 9, 1953, unpublished.
Isbell, Harris and Eisenman, Anna J., "The addiction liability of some drugs of the methadone series," J. Pharmacol. & Exper. Therap., 93, 305, 1948.
Isbell, Harris and Fraser, H. F., "The effects and addiction liabilities of the isomers of the 3-methyl ether of dromoran," J. Pharmacol. & Exper. Therap., 106, 397, 1952.
Denton, Jane E. and Beecher, Henry K., "New analgesics III. A comparison of the side effects of morphine, methadone and methadone isomers," J. Am. Med. Ass., 141, 1148, 1949.
Eddy, Nathan B., "Metopon hydrochloride. An experiment in clinical evaluation," Pub. Health Rep., 64, 93, 1949.
Eddy, Nathan B., "A new morphine-like analgesic," J. Am. Pharmaceut. Ass., Pract. Pharm. Ed., 8, 536, 1947.
Isbell, Harris, Wikler, Abraham, Eddy, Nathan B., Wilson, John L. and Moran, Clifford F., "Tolerance and addiction liability of 6-dimethylamino-4,4-diphenylheptanone-3 (Methadon)," J. Am. Med. Ass., 135, 888, 1947.
Denton, Jane E. and Beecher, Henry K., "New Analgesics. II. A clinical appraisal of the narcotic power of methadone and its isomers," J. Am. Med. Ass., 141, 1146, 1949.
Eddy, Nathan B., Touchberry, Caroline F. and Lieberman, Jacob E., "Synthetic analgesics. I. Methadone isomers and derivatives," J. Pharmacol. & Exper. Therap. 98, 121, 1950.
Keats, Arthur S. and Beecher, Henry K., "Analgesic potency and side action liability in man of heptazone, Win-116I-2, 6-methyldihydromorphine, metopon, levo-isometha-done and pentobarbital sodium, as a further effort to refine methods of evaluation of analgesic drugs," J. Pharmacol. & Exper. Therap., 105, 109, 1952.
Beecher, Henry K., Deffer, P. A., Fink, F. E. and Sullivan, D. B., "Field use of methadone and levo-isomethadone in a combat zone (Hamhung-Hungnam, North Korea)," U. S. Armed Forces Med. J., 2, 1269, 1951.
Randall, Lowell O. and Lehmann, G., "Analgesic action of 3-hydroxy-N-methylmorphinan hydrobromide (NU-2206)," J. Pharmacol. & Exper. Therap., 99, 163, 1950.
Zager, L. L., Sawtelle, W. W., Gross, E. G., Nagyfy, S. F. and Tidrick, R. T., "Observations on the use of a new analgesic agent, NU-2206 (3-hydroxy-N-methylmorphinan hydrobromide)," J. Lab. & Clin. Med., 34, 1530, 1949.
Fraser, H. F., Flanary, H. G., Houde, R. W. and Isbell, Harris, "Addiction liabilities of some drugs in the morphine series," Fed. Proc., 9, 273, 1950.
