Fw: Anniversary of methadone treatment for addiction. Untold savings in lives, suffering and spending.

Preston Peet ptpeet at nyc.rr.com
Fri Aug 12 02:04:35 EDT 2005

Oh boy, what a day for celebration, eh?

Peace and love,
Preston Peet

"Madness is not enlightenment, but the search for enlightenment is often mistaken for madness"
Richard Davenport-Hines

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----- Original Message ----- 
From: Andrew Byrne 
To: ajbyrne at ozemail.com.au 
Sent: Thursday, August 11, 2005 9:20 PM
Subject: Anniversary of methadone treatment for addiction. Untold savings in lives, suffering and spending.

Dear Readers, 


It is 40 years on 23rd August since the first report of methadone treatment for addiction.  Dole and Nyswander's seminal paper (below) is one of the most cited in the medical literature.  It stands as a model for all medical researchers, being a funded trial in a clinical research ward.  Although essentially a simple report of 24 Manhattan heroin addicts treated with a new intensive protocol utilising supervised oral daily methadone, it effectively defined the field for decades with its foresight and thoroughness.  Having only two early drop-outs, the 22 successful patients are described in detail, including hospital ward induction, average daily doses over 100mg, daily urine testing and, in addition to routine physical examinations, radio-iodine thyroid tests and bone marrow findings.  These pioneers also tested for physical coordination to determine safety at home and in the work place.  Patients were even given laxatives for the ubiquitous constipation.  


By 1970 Australian addicts were being offered similar treatment due to the frontier work of Dr Stella Dalton.  The treatment is now available in virtually every western country and is being introduced into some parts of the third world.  


The JAMA paper speaks for itself.  It remains a lasting tribute to its authors and acknowledged contributors: 


Published in Journal of the American Medical Association (JAMA) on 23 August 1965


A Medical Treatment for Diacetylmorphine (Heroin) Addiction


A Clinical Trial With Methadone Hydrochloride


Vincent P. Dole, MD, and Marie Nyswander, MD


A group of 22 patients, previously addicted to diacetylmorphine (heroin), have been stabilized with oral methadone hydrochloride. This medication appears to have two useful effects: (1) relief of narcotic hunger, and (2) induction of sufficient tolerance to block the euphoric effect of an average illegal dose of diacetylmorphine. With this medication, and a comprehensive program of rehabilitation, patients have shown marked improvement; they have returned to school, obtained jobs, and have become reconciled with their families. Medical and psychometric tests have disclosed no signs of toxicity, apart from constipation. This treatment requires careful medical supervision and many social services. In our opinion, both the medication and the supporting program are essential.



The question of "maintenance treatment" of addicts is one that is often argued but seldom clearly defined. If this procedure is conceived as no more than an unsupervised distribution of narcotic drugs to addicts for self-administration of doses and at times of their choosing, then few physicians could accept it as proper medical practice. An uncontrolled supply of drugs would trap confirmed addicts in a closed world of drug taking, and tend to spread addiction. This procedure certainly would not qualify as "maintenance" in a medical sense. Uncontrolled distribution is mentioned here only to reject it, and to emphasize the distinction between distribution and medical prescription. The question at issue in the present study was whether a narcotic medicine, prescribed by physicians as part of a treatment program, could help in the return of addict patients to normal society.


No definitive study of medical maintenance has yet been reported. The Council on Mental Health of the American Medical Association, after a thorough review of evidence available in 1957,1 concluded that "The advisability of establishing clinics or some equivalent system to dispense opiates to addicts cannot be settled on the basis of objective facts. Any position taken is necessarily based in part on opinion, and on this question opinions are divided." With respect to previous trials of maintenance treatment, the Council found that "Assessment of the operations of the narcotic dispensor between 1919 and 1923 is difficult because of the paucity of published material. Much of the small amount of data that is available is not sufficiently objective to be of great value in formulating any clear-cut opinion of the purpose of the clinics, the way in which they operated, or the results attained." No new studies bearing on the question of maintenance treatment have appeared in the eight years since this report was published. Meanwhile, various medical and legal committees have called for additional research.2,6


See also page 673 ['Dependence on Barbiturates and Other Sedative Drugs']


The present study, conducted under the auspices of the departments of health and hospitals, New York city, has yielded encouraging results; patients who before treatment appeared hopelessly addicted are now engaged in useful occupations and are not using diacetylmorphine (heroin). As measured by social performance, these patients have ceased to be addicts. It must be emphasized that this paper is only a progress report, based on treatment of 22 patients for periods of 1 to 15 months. Such limited study obviously does not establish a new treatment for general application. The results, however, appear sufficiently promising to justify further trial of the procedure on a larger scale.



The patients admitted to the program to date were men, aged 19 to 37, "mainline" diacetylmorphine users for several years with history of failure of withdrawal treatment. They have reported no substantial addictions to other agents (although most of them had used barbiturates or tranquilizers when narcotic drugs were unavailable), and they were not psychotic. Patients came from the streets, from drug withdrawal units, from referrals by social agencies and physicians who had heard of the program, and from recruitment of addicted friends by patients under treatment. Further details of their history are given in the Table.


Division of Program Into Three Phases.-PHASE 1.-The addict patients were stabilized with methadone hydrochloride in an unlocked hospital ward, given a complete medical workup, psychiatric evaluation, a review of family and housing problems, and job-placement study. After the first week of they were free to leave the ward for school, libraries, shopping, and various amusements-usually, but not always, with one of the staff. Patients lacking a high school diploma started in classes that prepare students for a high school equivalency certificate. For the present study the time in this initial phase was arbitrarily set at six weeks.


During this phase of hospitalization, the treatment unit was kept small (four to nine patients). This was felt necessary because most patients started the treatment with serious anxieties and doubts. The limitation of patient load allowed the staff to individualize the daily ward activities and deal with the special problems of each patient.


PHASE 2.-This began when subjects left the hospital and became outpatients, returning every day for methadone medication. They were asked to drink their medication in the presence of a clinic nurse, and to leave a daily urine specimen for analysis. When indicated, this rule has been relaxed; reliable patients who have been on the program for several months have been given enough medication for a weekend at home or a short trip. Continued contact with the hospital staff was provided as required. The most important services needed during this phase of treatment were help in obtaining jobs, housing, and education.


PHASE 3.-This phase is the goal of treatment, the stage in which an ex-addict has become a socially normal, self-supporting person. The two patients who are considered to have arrived at this phase are still receiving maintenance medication since the physicians in charge of their treatment feel that withdrawal at this time would be premature. Supervision of their medication is as careful as in phase 2; the only distinction between patients in phases 2 and 3 is in the degree of social advancement.


PHASE 1A.-This phase designates a special group of four patients who are being maintained on high doses under close and continuing observation to reveal any delayed toxic effects of methadone (Table). So far, none have been found. These patients live on a metabolic ward, and so are still classified in phase 1, but as measured by social adjustment they have progressed to phase 2 or 3, since all are either employed or going to school. The ward serves mainly as their residence, which they are free to leave as they wish subject only to the general routine of hospital activities.


Narcotic Medication.-Patients have differed markedly in tolerance to narcotics at the beginning of treatment, and in the rate with which they have adapted to increasing doses of medication. Individualization of treatment thus has been necessary. A rough estimate of initial tolerance was made from each new patient's history of drug usage, with allowance for exaggeration since addicts coming to a maintenance program usually fear that physicians will not prescribe enough medication, and with recognition of the fact that the number of "bags" used by an addict is not a reliable measure of narcotic tolerance. The diacetylmorphine content of a "bag" obtained on the street today is low and variable. This estimate provided a guide to initial dosage, but the only sure way to measure tolerance is to observe the reaction to test doses of narcotic drugs. The schedule, therefore, differed for each patient.


On admission patients usually have shown mild or moderately severe symptoms of abstinence, the last shot of diacetylmorphine having been taken some hours before. These patients were relieved promptly by one or two doses of morphine sulfate (10 mg) or dihydromorphone (Dilaudid) hydrochloride (4 mg), given intramuscularly, and then started on oral methadone hydrochloride therapy (10 to 20 mg, twice daily). Patients coming to treatment without symptoms were started on a regimen of methadone without other medication, but were watched carefully for appearance of symptoms after admission. After the first 24 hours most patients could be maintained comfortably on the oral medication alone. The dose of methadone hydrochloride was increased gradually over the next four weeks to stabilization level (50 to 150 mg/ day). Two patients in whom tolerance at the expected rate failed to develop have been held at lower doses (Table). With some patients, treated early in the study, the buildup of dosage was too rapid; they became overly sedated for a few days, and two of them had transient episodes of urinary retention and abdominal distention. Other patients, given too little, have become abstinent, exhibiting malaise, nausea, sweating, lacrimation, and restlessness. With more accurate prescription, patients have not become euphoric, sedated, or sick from abstinence at any stage of treatment. They have simply felt normal, and have not asked for more medication.


After the patients reached maintenance level, the morning and evening doses were combined by progressive reduction of the evening medication with an equal addition to the methadone taken in the morning. After discharge from the hospital patients could thus be maintained by a single daily visit to the outpatient clinic. The patients who have had difficulty in spanning a 24-hour period with a single dose have been given medication to take at home; this has been a minor problem, limited to those who could visit the clinic only in the evening. In all cases it has been made clear to the patients (and accepted by them as a condition of treatment) that the amount of medication and the dosage schedule were the responsibility of the medical staff. Physicians did not discuss dosage with the patients, although of course they listened carefully to any report of symptoms that might suggest excess or lack of medication.


Laboratory Control.-The urine of every patient was collected daily in the hospital and at each clinic visit, to be analyzed for methadone, morphine (the chief metabolite of diacetylmorphine), and quinine (a regular constituent of the street "bag"). The thin layer chromatographic method of Cochin and Daly7 was used, after preliminary extraction of the alkaloids from urine with cation exchange resin. The sensitivity of the procedure was such that it would give a definite positive if a patient had taken an average "bag" of diacetylmorphine during the preceding 24 hours.



The most dramatic effect of this treatment has been the disappearance of narcotic hunger. All of the patients previously had made efforts to remain drug-free after withdrawal, but were unable to resist the craving. Drug hunger became intolerable for most of them shortly after discharge from withdrawal unit and return to their neighborhood. It became especially severe when they were exposed to emotional stress. With methadone maintenance, however, patients found that they could meet addict friends, and even watch them inject diacetylmorphine, without great difficulty. They have tolerated frustrating episodes without feeling a need for diacetylmorphine. They have stopped dreaming about drugs, and seldom talk about drugs when together. Patients have even become so indifferent to narcotics as to forget to take a scheduled dose of medication when busy at home.


The extent to which the patients have ceased to behave as addicts, and their reliability in reporting illegal drug use, were verified by the results of urinanalysis. Negative results in almost all analyses showed that use of diacetylmorphine has been rare and sporadic, although the patients have had ample exposure to addict friends and pushers. Remarkably, the episodes of drug taking were reported by the patients spontaneously, and their reports have correlated with the laboratory evidence.


An interesting phenomenon, which has been seen in several patients, was the production of symptoms typical of drug deficiency by acute emotional stress. Anxiety in some susceptible patients caused malaise, nausea, yawning, and sweating, indistinguishable from the effects of abstinence, even though the patients were being maintained on large doses of medication. After experiencing relief with reassurance but without additional medication, susceptible patients have become less alarmed by these symptoms, and the episodes have occurred less frequently. In two other patients symptoms suggesting abstinence have appeared in the course of mild respiratory-tract infections. These symptoms, not associated with anxiety, were difficult to evaluate, but in any event disappeared in a few days without need for increase in medication. These observations suggest that the effectiveness of methadone can vary with changes in psychological and metabolic state.


The degree of tolerance established by methadone was titrated in six patients by giving diacetylmorphine, morphine, dilaudid, or methadone intravenously in a double-blind study. The drugs were given in randomized order and various doses six hours after the last administration of methadone. Stabilization with methadone, as here described, was found to make patients refractory to 40 to 80 mg diacetylmorphine (which would cost $10 to $25 if purchased on the street). Larger amounts were not systematically tested; probably blocking would extend to greater doses since two patients with high tolerance showed little reaction to intravenous injection of 200 mg of diacetylmorphine-a huge amount, possibly enough to kill a nontolerant individual.


Unscheduled, but perhaps necessary, experiments in drug usage were made by four patients. These subjects found that they did not "get high" when "shooting" diacetylmorphine with addict friends on the street. Both the patients and their friends were astounded at their lack of reaction to the drug. They discontinued these unrewarding experiments without need for disciplinary measures, and have discouraged other patients from repeating the experiment. So long as patients take methadone as scheduled, they apparently cannot feel the euphoria of an addict taking a street bag of diacetylmorphine.


Complications.-The chief medical problem has been constipation. The tonus of the sigmoid and the defecation reflex remain depressed even in patients with high tolerance to the narcotic effects of methadone, while the motility of the upper gastrointestinal tract appears to be unaffected. Five patients, given a barium sulfate meal and followed with daily x-ray examinations for a week, showed normal or only slightly delayed passage of barium through the small intestine, but in three of the five, the evacuation of barium from the colon was abnormally slow. Fecal impaction has occurred when patients have made no effort to defecate for several days. Patients therefore were instructed to take a hydrophilic colloid every day, and a supplementary laxative or enema if bowels have not moved for three days. With these precautions patients have had no further difficulty.


Apart from constipation, patients have shown no major ill effects ascribable to use of methadone. The tendency of addicts to leukocytosis (9,000 to 14,000 white blood cells/cu mm with 60% to 80% polymorphonuclear cells10 continued, apparently unaffected by this medication. Bone marrow biopsies in four patients after eight months of treatment were normal. No effect of methadone on renal function was disclosed by repeated urinanalyses. Liver-function tests, when originally normal, remained so. Results of basal metabolic rate, thyroid uptake of sodium iodide I 131, red blood cell uptake of labelled triiodothyronine, and plasma protein-bound iodine were normal in three patients who had been stabilized on methadone hydrochloride (100 to 150 mg/day) for four to six months. Some patients have reported excess sweating in hot weather, but no one has been unable to work for this reason. Mental and neuromuscular functions appear unaffected. Patients have performed well in school and at various jobs. Studies of motor skill (accuracy in tracking moving targets) showed normal coordination. We have not yet been able to find a medical or psychological test capable of distinguishing patients on methadone therapy from normal controls. They can, of course, be distinguished by urinanalysis.

There has been no problem so far in holding patients. Only two of the patients who started treatment have been discharged. These uncooperative and disruptive psychopaths were transfered to withdrawal units. Two others who were admitted specifically for tolerance tests at an early stage of the study were returned (as originally planned) to the withdrawal unit from which they came; both subsequently have asked to return to the program. A fifth patient signed out after only four days on the ward, and also asked to return.



Previous efforts to treat addict patients with narcotic medication have been handicapped by lack of sufficiently long-acting agents. The Council's report noted that in 1919 to 1923 experience, "in all instances it was eventually found necessary to give drugs to addicts for self-administration." This is inherent in the pharmacology of parenterally administered morphine, which was used in these clinics and would probably apply to other agents with short periods of action such as diacetylmorphine, dihydromorphine, or meperidine. If addict patients are to be maintained with any of these drugs, they would need several injections per day; otherwise they would return to the street for additional drugs.


Projected into large-scale treatment, a medical use of short-acting narcotic drugs would require dispensaries staffed to give thousands of injections per day, with rooms or park benches in the neighborhood for addicts to wait between shots. Alternatively, physicians would have to yield control of drug administration to the addicts themselves. Neither alternative is acceptable. With methadone, however, the situation is much different since patients can be stabilized with a single daily dose, taken orally, under medical control. Maintenance of patients with methadone is no more difficult than maintaining diabetics with oral hypoglycemic agents, and in both cases the patient should be able to live a normal life. 


We believe that methadone has contributed in an essential way to the favorable results, although it is quite clear that giving of medicine has been only part of the program. This drug appears to relieve narcotic hunger, and thus free the patient for other interests, as well as protect him against readdiction to diacetylmorphine by establishing a pharmacological block. A previous attempt by one of us (M.N.) to treat addict patients without narcotic medication ended in failure. Other clinics, attempting to rehabilitate patients after withdrawal, have had equally poor results. These, however, are indirect arguments. When the treatment program is sufficiently well established, the necessary control studies with social support, but without medication, must be made.


This study was supported by the Health Research Council grant U-1501 of New York city, and by the National Association for Prevention of Addiction to Narcotics.


Major contributions to this investigation were made by the following: Mary Jeanne Kreek, MD, bone marrow biopsies and tests of narcotic tolerance; Joyce Lowinson. MD. and George Lowen, MD, expansion of the program at Manhattan General Hospital; Nathan Poker, MD, measurements of intestinal motility; David Becker, MD, and Eugene Furth, MD. tests for thyroid function; and Norman Gordon, MD, Alan Warner, and Ann Henderson, measurements of motor skills of patients and ratings with intelligence tests and mood scales. 


Generic and Trade Names of Drug 

Sodium iodide I 131-Iodotope-1 131, Oriodide-131, Radiocaps131, Theriodide-131, Tracervial-131.



1. Council on Mental Health: Report on Narcotic Addiction, JAM/i 165:1707-1713 (Nov 30); 1834-1841 cDec 7 1968-1974 (Dec 14) 1957.

2. Joint Committee of American Bar Association and American Medical Association of Narcotic Drugs. Interim and Final Reports: Drug Addiction: Crime or Disease? Bloomington, MD: Indiana University Press, 1961.

3. Presidents Advisory Commission on Narcotic and Drug Abuse. Appendix 1. Final Report, US Government Printing Office. Nov 1963.

4. New York Academy of Medicine, Committee on Public Health: Report on Drug Addiction: II, Bull NY Aced Med 39:417-473 (July) 1963.

5. Eldridge, W.B.: Narcotics and Law, Chicago: American Bar Foundation, 1962.

6. National Council on Crime and Delinquency. Advisory Council of Judges. Narcotics Law Violations: Policy Statement, New York. 1964.

7. Cochin. J.. and Daly, ,J.: Rapid Identification of Analgesic Drugs in Urine With Thin-Layer Chromatography, Experientia 18:294-295 (June 15) 1962.

8. Light. AB., and Torrance. E.G.: Opium Addiction: VI. Effects of Abrupt Withdrawal Followed by Readministration of Morphine in Human Addicts With Spectral Reference to Composition of Blood, Circulation, and Metabolism, Arch Intern Med 44:1-16 (July) 1929.

9. Ishell, H.. et al: Liability of Addiction of 6-Dimethylamino-

4.4-diphenyl-3-heptanone (Methadon, "Amidone" or "10820") in Man. Arch Intern Med 82:362-392 (Oct) 1948.

10. Berle, B., and Nyswander, M.: Ambulatory Withdrawal Treatment of Heroin Addicts, New York J Med 64:1846-1848 (July) 1964.



Dole VP, Nyswander ME. A medical treatment for diacetylmorphine (heroin) addiction. J Amer Med Assoc 1965;193:646-50  


Table 1. (legend) see attached xls file. 


Maintenance Therapy of Ex-Addicts With Methadone Hydrochloride, Summary of First

15 Months (February 1964 to May 1965). 


*For comparison with other treatment series, patients classified into three groups: Western European ancestry (E), Puerto Rican and Cuban (F), and Negro (N).


~ Age first used diacetylmorphine (FD); age at admission (A).


ð Number of admissions to Federal Hospital-Lexington, Ky (F), state hospitals-Manhattan State, Central Islip (S), municipal hospital -Manhattan General, Metropolitan, Riverside (M), private clinics and groups, including Synanon (P).


§ All but two patients were employed at time of admission. Job indicated is best position ever held, 


Time in Army (A), Navy (N), Marines (M), or Air Force (AF).


¶ Dose methadone hydrochloride given orally, mg/day.


# Phases of treatment: la-four patients, residents on metabolic ward of Rockefeller Institute; 1-new patients being stabilized on methadone therapy, they sleep in hospital but may leave during day for school, shopping, or job; 2-patients newly discharged, living at home or rooming house, needing social support; 3-ambulatory patients who are self-supporting. 


** High school equivalency status: If not a high school graduate, each patient was encouraged to enroll in night school to prepare for high school equivalency certificate. Those who have completed this course, passed examination, and received certificate are indicated by 'Cert'; those now in night school indicated by NS."



Posted by Andrew Byrne, Sydney addiction doctor. 


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