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Journal of Psychoactive Drugs Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ujpd20
A Brief History of Methadone in the Treatment of Opioid Dependence: A Personal Perspective J. Thomas Payte
a
a
Drug Dependence Associates , 3701 West Commerce Street, San Antonio , Texas , 78207 Published online: 20 Jan 2012.
To cite this article: J. Thomas Payte (1991) A Brief History of Methadone in the Treatment of Opioid Dependence: A Personal Perspective, Journal of Psychoactive Drugs, 23:2, 103-107, DOI: 10.1080/02791072.1991.10472226 To link to this article: http://dx.doi.org/10.1080/02791072.1991.10472226
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
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Opioid Dependence: A Personal Perspective J. Thomas Payte, M.D.* Abstract- Starting at the latter part of the nineteenth century and through the early twentieth century, events are reviewed to provide a sense of the climate and setting in which early methadone research was conducted. The discovery of methadone by the Germans in the later stages of World War IT is described. At that time, methadone was not recognized to be a narcotic analgesic. The first report of the properties of methadone published in the United States in 1947 is summarized, and its early use in the treatment of the opioid abstinence syndrome is noted. However, the utility of methadone as a maintenance drug was not recognized unti114 years later. Despite strong resistance from the U.S. Bureau of Narcotics, research progressed from the recognition of the unique properties of methadone to substantial clinical application. Finally, methadone is placed in a current context describing a second wave of acceptance based not solely on the reduction of crime but on the prevention of the spread of AIDS. Keywords- addiction, AIDS, heroin, methadone, narcotics, opioids
During the nineteenth century, addiction was not associated with crime to any extent. However, opium smoking was an exception. Opium eating (oral ingestion of opium) was noted among the respectable classes rather than among criminals (Lindesmith 1968). Opioid addiction was viewed with less disdain than alcoholism, and opioids were also promoted as a preferable treatment for intractable alcoholism. This contrast was well illustrated by Black in 1889, as cited by Lindesmith:
ulace and even many physicians think very differently, but this is because they have not thought as they should upon the matter. On the score of economy, the morphine habit is by far the better. The regular whiskey drinker can be made content in his craving for stimulation, at least for quite a long time, on two or three grains of morphine a day, divided into appropriate portions, and given at regular intervals. If purchased by the drachm [dram) at fifty cents, this will last him twenty days. Now it is safe to say that a lilc.e amount of spirits for the steady drinlc.er cannot be purchased for two and one half cents a day, and that the majority of them spend five and ten times that sum a day as a regular thing. On the score, then, of a saving to the individual and his family in immediate outlay, and of incurred disability to fearful diseases and the lessened propagation of pathologically inclined blood, I would urge the substitution of morphine instead of alcohol for all to whom such a craving is an incurable propensity. In this way I have been able to bring peacefulness and quiet to many distu!bed and distracted homes, to keep the head of the family out of the gutter and out of the lock -up, to keep him from scandalous misbehavior and neglect of his affairs, to keep him from the verges and actualities of delirium tremens and horrors, and, above all, to save him from committing, as I veritably believe, some terrible crime that would cast a lasting and deep shadow upon an innocent and worthy family circle for generation after
The only grounds on which opium in lieu of alcohol can be claimed as reformatory are that it is less inimical to healthy life than alcohol, that it calms in place of exciting the baser passions, and hence is less productive of acu of violence and crime; in short, that as a whole the use of morphine in place of alcohol is but a choice of evils, and by far the lesser. To be sure, the pop-
•Chairperson, Committee on Methadone Treatment, American Society of Addiction Medicine; Founder and Medical Director, Drug Dependence Associates, 3701 West Commerce Street, San Antonio, Texas 78207.
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generation. Is it not the duty of a physician when he cannot cure an ill, when there is no reasonable ground for hope that it will ever be done, to do the next best thing- advise a course of treatment that will diminish to an immense extent great evils otherwise irremediable? . .. 'The mayors and police courts would almost languish for lack of business; the criminal dockets, with their attendant legal functionaries, would have much less to do than they now have - to the profit and well-being of the community. I might, had I time and space, enlarge by statistics to prove the law-abiding qualities of opium-eating peoples, but of this anyone can perceive somewhat for himself, if he carefully watches and reflects on the quiet introspective gaze of the morphine habitue and com pares it with the riotous devil-may-care leer of the drunkard.
late. The medical profession was well out of the picture and remained absent for about 40 years. As physicians were removed from the scene, the illicit drug market began to prosper in the absence of competition (Lindesmith 1%8). During the time that cases were being made against physicians, federal agents relied heavily on addicted informers who cooperated in exchange for narcotics supplied by the agents. The amount of narcotics supplied by government agents to informers was said to be small, but this was a necessary expedient to law enforcement because the informers were needed to make cases against doctors. This practice of police providing narcotics to addicts was sanctioned, while at the same time physicians were being arrested for prescribing them to addicts (Lindesmith 1965). By the time the United States entered World War II, narcotics addiction had all but vanished (Inciardi 1984). This was not attributed to legislative, legal enforcement or medical efforts, but was a result of interrupting supplies of opium from Asia. In the August 14, 1942, issue of Time an editorial suggested that the war was probably the best thing that ever happened to drug addicts. There has been, and perhaps still is, a popular belief that methadone was developed in response to a shortage of opium during the later stages of the war. Hitler was assumed to have instructed his scientists to quickly develop an oral substitute for morphine. The scientists then discovered amidon or amidone, later to be called methadone, which was given the trade name Dolophine, said to be derived from Adolph. It would seem much more likely, however, that Dolophine was derived from dolor for pain and fin for end: pain end. In reality, methadone was discovered in the course of work on spasmolytic compounds. It was discovered by I.G. Farbendustrie at Hoechst-am Main, Germany. Lacking any resemblance to known compounds, its narcotic analgesic properties were not expected. In spite of the morphine shortage, methadone was not used as an analgesic until the . postwar period (Lenz et al. 1986). In the December 6, 1947, issue of the Journal oft he American Medical Association, an article by Isbell and colleagues presented the results of both animal and human studies with methadone in relation to tolerance, physical dependence, and abstinence syndrome. They reported that four men received injections of methadone four times daily (q.i.d.) for 180 days, with daily doses ranging from 200800 mg. Doses were reduced for two subjects who were on 200 mg and 150 mg q.i.d. Induration and inflammation at the injection sites prompted the reduction. One subject in another series had his dose reduced from 100 mg q.i.d . to 50 mg q.i.d. "because of the appearance of signs of toxicity." Substitution of methadone for morphine was considered and the characteristics of abstinence were discussed and compared. The dosage amounts have been provided for the benefit of homeopathic-minded, methadone main-
The passage of the Harrison Act in 1914 marked the beginning of a period of profound change in the problem of narcotics in the United States. On the surface it appeared to be an effort to generate revenue, and, through registration and record keeping, exercise some control over the flow of drugs; however, it did not provide for punishment of the user of drugs. Moreover, the inclusion of references to "legitimate medical purposes," "professional practice," and "prescribed in good faith" would suggest that the Act was not intended to deter the practitioner in any way (Lindesmith 1968). Due to a series of interpretations and decisions, drastic changes were to occur. By 1938 approximately 25,000 physicians had been arraigned on narcotics charges and 3,000 served penitentiary sentences (Straus 1965). In 1915, the decision in the case of United States v. lin Fuey Moy is said to have created an entirely new class of criminals because physicians became the only remaining legal source of narcotic drugs, which was eventually eliminated by later decisions (Lindesmith 1965). In response to the resultant dwindling role of the practicing physician in the treatment of narcotics addicts, more than 40 clinics emerged. For the most part they were operated as governmental entities. It is not clear if the clinics were perceived as a threat to the new and growing business of illicit narcotics, but their presence was not to be tolerated. The Treasury Department eventually succeeded in closing all of them (Straus 1965). In 1922, the Behrman case determined that it was a crime for a physician to prescribe narcotics to an addict, regardless of the intentions of the prescribing physician (Lindesmith 1965). However, provisions were made for specified institutions to use narcotics in a graded reduction of dose. Shortly after the Behrman case, Dr. Charles 0. Linder prescribed four tablets of a narcotic to an informer who was an addict. Dr. Linder was arrested and convicted. However, about two years after losing his medical license and $30,000 (1920 dollars), he was exonerated by the Supreme Court in 1925. The reversal of the decision in this case recognized addicts as being diseased and proper subjects for medical treatment (Lindesmith 1965). However, the 1925 Linder decision was too little too JourNJI of Psychoactive Drwgs
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tenance treatment (MMT) program physicians who feel that doses of 80-100 mg are massive and dangerous. There was no reference to the use of methadone as a treatment for morphine abstinence (which apparently came a short time later) nor was there mention of oral methadone. In my experience, oral methadone and intravenous (IV) methadone are, acutely at least, two different drugs. Given orally, methadone is subject to extensive first-pass extraction by the liver where it is stored unchanged for later release. When given intravenously, being highly lipophilic, methadone behaves more like heroin. This acute difference diminishes with time. One can only wonder if Isbell and colleagues would have reached different conclusions had they used oral methadone in their 140- to 180-day studies. Oral methadone was established as a treatment for the opioid abstinence syndrome in U.S. Public Health Service hospitals by 1950 (Maddux 1989). The discovery of methadone's unique pharmacokinetic properties did not occur until 14 years later. Meanwhile, on the postwar legislative front, the Boggs Bill was passed in 1951 and later the Narcotic Drug Control Act of 1956. These were efforts to facilitate arrests and convictions, while providing for harsher penalties for those involved with narcotics. In the 1960s, this climate reflected that organized medicine continued to be withdrawn from involvement in the treatment of addiction. There was residual fear among physicians to become involved and there was little motivation to do so. This aversion or lack of interest may be attributed to the total change in the perceived image and character of the contemporary opioid-dependent person as a criminal in contrast to the benign acceptance of the nineteenth century opium eater. I began working with street heroin addicts in the early 1960s and quickly learned not to discuss this activity with my colleagues. Illicit traffic in opioids was thriving, the heroin epidemic was in full swing, and the middle-class junkie had emerged. It was simple to decide where to send a patient for hospital care. All women and men east of the Mississippi River went to the U.S. Public Health Service hospital in Lexington, Kentucky; men west of the Mississippi went to a similar federal hospital in Fort Worth, Texas. In a feature article (Hentoff 1965) in the New Yorker, Dr. Marie Nyswander stated that "the present situation is so damn senseless and tragic. Wait- someone put it more accurately: 'The American narcotics problem is an artificial tragedy with real victims.'" By the late 19 50s and early 1960s, it was clear, at least to some people, that the prohibition model was not working. The conventional treatment of detoxification and discharge was not working. It is no wonder that interest in pharmacological/medical maintenance treatments was revived and enhanced, even though these treatments had been completely dismissed by law enforcement agencies and considered improper by Jourrwl of Psychoactiv~ Drwgs
the medical establishment. In November 1963, Dr. Vincent Dole was awarded a research grant from the New York City Health Research Council (Waldorf 1973). It is very likely that anyone else would not have succeeded, but Dole was a well-established research scientist with the best of credentials and reputation. Also, he had the courage to withstand the pressures of the powerful U.S. Bureau of Narcotics. For example, when told by an agent that he was breaking the law and that they would put him out of business, he invited them to take him to court so that a proper ruling on the matter could be made (Courtwright, Joseph & DesJarlais 1989). The following year, MMT was discovered. Most of the accounts of the events surrounding this discovery are in general agreement. A meaningful account of the early days was provided by Dr. Mary Jeanne Kreek at an informal gathering of some members of the American Society of Addiction Medicine Methadone Treatment Committee in Miami on February 3, 1989. She had been there when history was being made. Back in 1964, Vince, Marie, and I wanted to be absolutely sure that reports from Lexington, Britain, and elsewhere were indeed reproducible in our hands and correct. That is, if you used morphine (we used morphine and not heroin) to treat addiction, even if you used four doses per day, taking into account what was thought to be the pharmacokinetic profile, and mind you, we couldn't measure blood levels of morphine or methadone back then, one could not achieve a steady state. We tried to see if we could stabilize patients on a given dose of morphine, and, the answer, as it had been in everyone else's hands, from the early days of Lexington onward, that increasing doses of morphine had to be administered. We then turned to a drug for which there were indicaton, primarily from pain research plus some short-term detox experience, that suggested it might be longer acting, again not proven pharmacokinetically, and that was methadone, and it had the second advantage of being orally effective. We raised people up to a dose ... what we found, and found it within the first three or four weeks, but really saw it in the first six months to a year, you could bring a person up to a dose that was an adequate treatment dose . .. and level them off at that dose and they would not need any more. They would not need any more to prevent abstinence symptoms at the end of a dosing interval which was soon determined to be 24 houn, and they would not need any more to prevent craving. We then found that patients, one year, two yean, three yean, and four yean still didn't need any more. By that time good critics were saying, "Maybe you have rehabilitated those people so well that it is not even needed any more ... which was a very good question. So on a blinded basis, first single then double, we would reduce people ... and reduce their dose down very slowly to a certain point that we would watch their symptomatology. We found that most people did not have any problem until they got to a certain point, and when we would fmally break the code it would be something between 15 and 35 mg. At that point they would become symptomatic at the end of the 24-hour dosing interval. If we tried to go further than that then the symptoms could be seen at every subsequent dose lowering. We stopped there, and when we would go back up over their critical threshold, which was quite individualized, they would be fme. Sometimes we would have up and down and up and down on a double-blinded basis and not 105
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and also due to a lot of poorly qualified but eager or opportunistic people anxious to solve thenarcotics problem by handing out methadone. "That's when things became disorderly," Dole remarked. 3. Dole made the point that effective rapid expansion could occur with medical competence. He gave the example of Dr. Robert Newman bringing in 20,000 new patients in an efficient, orderly manner with good data collection by a staff that enjoyed excellent morale. 4. The situation led to what Dole called the "regulatory counterattack" that occurred around 1973. The federal government saw the invitation and chose to "reenter the field in a vigorous way, to take command of the whole business and to set up regulations that ... have to a large extent damaged the programs today." Others, especially clinicians using methadone treatment, continue to operate under the restrictions and busywork that resulted from this unprecedented intrusion into the practice of medicine. 5. Along with a lack of understanding of methadone maintenance treatment and opioid addiction some saw methadone as an expedient means to engage people in treatment and to retain them long enough to cure the underlying problems through psychotherapy, prayer or whatever, at whi ch time methadone could be discontinued . Dole referred to this as a kind of hybrid thinking. This thinking was adopted by the regulators who then missed the very basis for methadone maintenance and in the process of regulation by political and ideological compromise turned it all upside down to make abstinence, not rehabilitation, the goal of treatment. The early rapid expansion of methadone maintenance was tolerated by the public mostly for its prospect as areduction in crime. I have often wondered how it might have been if methadone had been publicized as a benefit only to the addict, with no direct benefit to society in the reduction of crime. In the 1970s, public and governmental concerns shifted to the economy. Funded programs ceased to expand, and many faced funding reductions. One of the programs I was involved with at that time was forced to return over 100 addicts to the streets. As might be expected, the ones that were the easiest to treat and who made the program look good were retained, while the sicker and more complicated patients were the flfst to be terminated. At that point in my career I withdrew from the public sector to my private practice, where I hoped to be shielded from the effects of mood swings on the part of the funding powers. As the government reduced its involvement in and commitment to the treatment business, private enterprise moved in. The quality of care provided among this pro-
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break the code, just say 10 the pharmacist; up or down, and the pharmacist at Rockefeller would go up or down accordingly. 'This showed us that, in fact, they still needed methadone, that they were still very dependent on it in terms of prevention of absti nence and craving, but that the full treatment dose that they were on probably wasn't essential to prevent the craving and the ab stinence; however each person would have their own threshold. That showed us that it still was doing something, it wasn't that they had recovered to the point that they no longer had any need for the pharmacologic agent.
Other accounts of the discovery emphasize the dramatic change in behavior. During the two months of attempted morphine maintenance, receiving up to 600 mg parenterally daily, the two patient-subjects were described as being very passive, just waiting patiently for the next injection. With the substitution of 150-180 mg methadone daily by mouth, the patients became active, interested, engaged in purposeful activity. Unger (1985) wondered whether the "invention" of methadone maintenance would have occurred if those first few patients had not been motivated to make some changes. The first two became six, then 22, and by October 1968, 1,139 were in the program. In August 1965, Dole and Nyswander gave a cautious and restrained report of the clinical trials with the first22 patients. The response by the media was not so cautious and restrained, which probably helped excite the critics of any form of medical maintenance treatment. The controversy was born and lives to this day. It would be more accurate to describe the present-day debate as philosophical and ideological differences rather than a true controversy, which is defined as a disputation over a matter of opinion. Today the safety, effectiveness, and value of properly applied MMT is no more controversial than is the assertion that the earth is round . Nevertheless, there was heated philosophical debate during which clinical experience and the derived scientific data were ignored. This phenomenon prompted Newman ( 1977) to write a chapter titled "The Irrelevance of Success" in his book about MMT. The following outline traces the attitudes of the federal government toward methadone maintenance; it draws heavily on Dole's taped interview that appeared in the methadone maintenance section of Addicts Who Survived: An Oral History of Narcotic Use in America,l923-1965 (Courtwright, Joseph & DesJarlais 1989). 1. The early results were most encouraging. Dole described this period from 1965 to 1970 as the honeymoon stage. This was in spite of the continued presence of the U.S. Bureau of Narcotics and other agencies who "carped, infiltrated, and attempted to discredit the program . ... " 2. The early 1970s saw a rapid expansion of methadone maintenance, which was due partly in response to pressures from the Nixon White House Journal of Psychoactive Drugs
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no one knows much about the quality of many programs throughout the country. Work is now under way to define elements of quality in programs, to establish performancebased standards of care, and to develop an MMT quality assurance system. It is very likely that significant changes will occur in MMT in the 1990s. The need is both substantial and urgent, but history has shown the folly of expanding service beyond the capacity to staff programs with competent, well-trained people. There is potential to do a great deal of good or a great deal of harm . It is the responsibility of physicians, psychologists, nurses, counselors, and administrators to be informed and involved in this process to ensure the best possible treatment of the addict-patient toward a goal of full rehabilitation. It is no longer sufficient to take care of patients. Treatment providers must also become teachers, public relations workers, politicians, and advocates for all patients who want and need treatment.
liferation of programs could be described as uneven. Some less than ideal programs seemed to attract a great deal of attention, while some very excellent programs quietly went about their business maintaining a low profile. For whatever reasons, methadone maintenance treatment to this day continues to have an image problem. In the midst of a new wave of acceptance, this time based on the relationship between AIDS and IV heroin use and the clearly demonstrated effectiveness of methadone maintenance in reducing the spread of AIDS (Cooper 1989), it appears that MMT has survived a difficult period of growth and maturation to now experience the process of increasing legitimization (Zweben & Payte 1990). However, that process is quite fragile. While there are many excellent programs, others are lacking quite severely. That MMT is potentially both effective and safe is no longer in question. However, Ball and colleagues ( 1988) have shown that marked differences exist in the effectiveness of various programs. It is probably true that
REFERENCES Ball, J.C.; Lange, W.R. ; Myen, C .P. & Friedman, S.R. 1988. Reducing the risk of AIDS through methadone maintenance treatment JoUI'NJ) of Health and Social Behavior Vol. 29 : 214-226. Black, J.R. 1889. Advantages of substituting the morphia habit for the incurably alcoholic. CinciMati La11cet-Ciinic Vol. 22: 537-541. Cooper, J.R. 1989. Methadone treatment and acquired inununodeficiency syndrome. Journal of the Amuica11 Medical Associatio11 Vol. 262(12): 1664-1668. Courtwright, D.; Joseph, H. & DesJarlais, D. 1989. Addicts Who Survived : A11 Oral History ofNarcotic Use in America,J923-1965. Knoxville: University of Tennessee Press. Dole, V.P. & Nyswander, M. 1965. A medical treatment for diacetylmorphine (heroin) addiction - a clinical trial with methadone hydrochloride. Jowrnal of the America11 Medical Associatio11 Vol. 193(8): 646-650. Hentoff, N. 1965. Profiles: The treatment of patients-! : Dr. Marie Nyswander. New Yorlru July: 32-75. Inciardi, J.A. 1984. The War 011 Drugs: Heroi11, Cocaine, Crime and Public Policy. Palo Alto, California: Mayfield. Isbell, H.; Wikler, A.; Eddy, N.B. ; Wibon, J.L. & Moran, C .F. 1947. Tolerance and addiction liability of 6-dimethylam.i.no-4-4-diphenylheptanon-3 (methadon). Journal of the America11 Medical
Jowrnal of Psychoactive Drugs
Associatio11 Vol. 135: 888-894.
Lenz, G.R; Evans, S.M.; Walters, D.E. & Hopfmger, A.J. 1986. Opiates. New York: Academic Press. Lindesmith, A.R. 1968. Addictio11 and Opiates. Chicago: A!dine. Lindesmith, A.R. 1965. The Addict and the Law. Bloomington: Indiana University Press. Maddux, J.F. 1989. Personal communication, April. Department of Psychiatry, University of Texas Health Science Center, San Antonio; former director, U.S. Public Health Service Hospital, Ft. Wonh, Texas. Newman, R.G. 19TI. Methadone Treatmefll in Narcotic Addictio11. New York: Academic Press. Straus, N., ill. 1965. Treatmefll Before Cure . New York : Nathan Straus
m. Unger, K.B. 1985. Methadone in the treatment of heroin addictioncurrent state of the an. Califorllia Society for the Treatme11t of Alcoholism and Other Drug Dependencies News Vol. 12(1). Waldorf, D. 1973. Careers i11 Dope. Englewood Cliffs, New Jersey: Prentice-Hall. Zweben, J.E. & Payte, J.T. 1990. Methadone maintenance in the treat· ment of opioid dependence- a current perspective. Wester11 Jountal of Medicine Vol. 152(5): 588-599.
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Journal of Psychoactive Drugs Publication details, including instructions for authors and subscription information: http://www.tandfonline.com/loi/ujpd20
A Brief History of Methadone in the Treatment of Opioid Dependence: A Personal Perspective J. Thomas Payte
a
a
Drug Dependence Associates , 3701 West Commerce Street, San Antonio , Texas , 78207 Published online: 20 Jan 2012.
To cite this article: J. Thomas Payte (1991) A Brief History of Methadone in the Treatment of Opioid Dependence: A Personal Perspective, Journal of Psychoactive Drugs, 23:2, 103-107, DOI: 10.1080/02791072.1991.10472226 To link to this article: http://dx.doi.org/10.1080/02791072.1991.10472226
PLEASE SCROLL DOWN FOR ARTICLE Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and should be independently verified with primary sources of information. Taylor and Francis shall not be liable for any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of the Content. This article may be used for research, teaching, and private study purposes. Any substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http:// www.tandfonline.com/page/terms-and-conditions
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Opioid Dependence: A Personal Perspective J. Thomas Payte, M.D.* Abstract- Starting at the latter part of the nineteenth century and through the early twentieth century, events are reviewed to provide a sense of the climate and setting in which early methadone research was conducted. The discovery of methadone by the Germans in the later stages of World War IT is described. At that time, methadone was not recognized to be a narcotic analgesic. The first report of the properties of methadone published in the United States in 1947 is summarized, and its early use in the treatment of the opioid abstinence syndrome is noted. However, the utility of methadone as a maintenance drug was not recognized unti114 years later. Despite strong resistance from the U.S. Bureau of Narcotics, research progressed from the recognition of the unique properties of methadone to substantial clinical application. Finally, methadone is placed in a current context describing a second wave of acceptance based not solely on the reduction of crime but on the prevention of the spread of AIDS. Keywords- addiction, AIDS, heroin, methadone, narcotics, opioids
During the nineteenth century, addiction was not associated with crime to any extent. However, opium smoking was an exception. Opium eating (oral ingestion of opium) was noted among the respectable classes rather than among criminals (Lindesmith 1968). Opioid addiction was viewed with less disdain than alcoholism, and opioids were also promoted as a preferable treatment for intractable alcoholism. This contrast was well illustrated by Black in 1889, as cited by Lindesmith:
ulace and even many physicians think very differently, but this is because they have not thought as they should upon the matter. On the score of economy, the morphine habit is by far the better. The regular whiskey drinker can be made content in his craving for stimulation, at least for quite a long time, on two or three grains of morphine a day, divided into appropriate portions, and given at regular intervals. If purchased by the drachm [dram) at fifty cents, this will last him twenty days. Now it is safe to say that a lilc.e amount of spirits for the steady drinlc.er cannot be purchased for two and one half cents a day, and that the majority of them spend five and ten times that sum a day as a regular thing. On the score, then, of a saving to the individual and his family in immediate outlay, and of incurred disability to fearful diseases and the lessened propagation of pathologically inclined blood, I would urge the substitution of morphine instead of alcohol for all to whom such a craving is an incurable propensity. In this way I have been able to bring peacefulness and quiet to many distu!bed and distracted homes, to keep the head of the family out of the gutter and out of the lock -up, to keep him from scandalous misbehavior and neglect of his affairs, to keep him from the verges and actualities of delirium tremens and horrors, and, above all, to save him from committing, as I veritably believe, some terrible crime that would cast a lasting and deep shadow upon an innocent and worthy family circle for generation after
The only grounds on which opium in lieu of alcohol can be claimed as reformatory are that it is less inimical to healthy life than alcohol, that it calms in place of exciting the baser passions, and hence is less productive of acu of violence and crime; in short, that as a whole the use of morphine in place of alcohol is but a choice of evils, and by far the lesser. To be sure, the pop-
•Chairperson, Committee on Methadone Treatment, American Society of Addiction Medicine; Founder and Medical Director, Drug Dependence Associates, 3701 West Commerce Street, San Antonio, Texas 78207.
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generation. Is it not the duty of a physician when he cannot cure an ill, when there is no reasonable ground for hope that it will ever be done, to do the next best thing- advise a course of treatment that will diminish to an immense extent great evils otherwise irremediable? . .. 'The mayors and police courts would almost languish for lack of business; the criminal dockets, with their attendant legal functionaries, would have much less to do than they now have - to the profit and well-being of the community. I might, had I time and space, enlarge by statistics to prove the law-abiding qualities of opium-eating peoples, but of this anyone can perceive somewhat for himself, if he carefully watches and reflects on the quiet introspective gaze of the morphine habitue and com pares it with the riotous devil-may-care leer of the drunkard.
late. The medical profession was well out of the picture and remained absent for about 40 years. As physicians were removed from the scene, the illicit drug market began to prosper in the absence of competition (Lindesmith 1%8). During the time that cases were being made against physicians, federal agents relied heavily on addicted informers who cooperated in exchange for narcotics supplied by the agents. The amount of narcotics supplied by government agents to informers was said to be small, but this was a necessary expedient to law enforcement because the informers were needed to make cases against doctors. This practice of police providing narcotics to addicts was sanctioned, while at the same time physicians were being arrested for prescribing them to addicts (Lindesmith 1965). By the time the United States entered World War II, narcotics addiction had all but vanished (Inciardi 1984). This was not attributed to legislative, legal enforcement or medical efforts, but was a result of interrupting supplies of opium from Asia. In the August 14, 1942, issue of Time an editorial suggested that the war was probably the best thing that ever happened to drug addicts. There has been, and perhaps still is, a popular belief that methadone was developed in response to a shortage of opium during the later stages of the war. Hitler was assumed to have instructed his scientists to quickly develop an oral substitute for morphine. The scientists then discovered amidon or amidone, later to be called methadone, which was given the trade name Dolophine, said to be derived from Adolph. It would seem much more likely, however, that Dolophine was derived from dolor for pain and fin for end: pain end. In reality, methadone was discovered in the course of work on spasmolytic compounds. It was discovered by I.G. Farbendustrie at Hoechst-am Main, Germany. Lacking any resemblance to known compounds, its narcotic analgesic properties were not expected. In spite of the morphine shortage, methadone was not used as an analgesic until the . postwar period (Lenz et al. 1986). In the December 6, 1947, issue of the Journal oft he American Medical Association, an article by Isbell and colleagues presented the results of both animal and human studies with methadone in relation to tolerance, physical dependence, and abstinence syndrome. They reported that four men received injections of methadone four times daily (q.i.d.) for 180 days, with daily doses ranging from 200800 mg. Doses were reduced for two subjects who were on 200 mg and 150 mg q.i.d. Induration and inflammation at the injection sites prompted the reduction. One subject in another series had his dose reduced from 100 mg q.i.d . to 50 mg q.i.d. "because of the appearance of signs of toxicity." Substitution of methadone for morphine was considered and the characteristics of abstinence were discussed and compared. The dosage amounts have been provided for the benefit of homeopathic-minded, methadone main-
The passage of the Harrison Act in 1914 marked the beginning of a period of profound change in the problem of narcotics in the United States. On the surface it appeared to be an effort to generate revenue, and, through registration and record keeping, exercise some control over the flow of drugs; however, it did not provide for punishment of the user of drugs. Moreover, the inclusion of references to "legitimate medical purposes," "professional practice," and "prescribed in good faith" would suggest that the Act was not intended to deter the practitioner in any way (Lindesmith 1968). Due to a series of interpretations and decisions, drastic changes were to occur. By 1938 approximately 25,000 physicians had been arraigned on narcotics charges and 3,000 served penitentiary sentences (Straus 1965). In 1915, the decision in the case of United States v. lin Fuey Moy is said to have created an entirely new class of criminals because physicians became the only remaining legal source of narcotic drugs, which was eventually eliminated by later decisions (Lindesmith 1965). In response to the resultant dwindling role of the practicing physician in the treatment of narcotics addicts, more than 40 clinics emerged. For the most part they were operated as governmental entities. It is not clear if the clinics were perceived as a threat to the new and growing business of illicit narcotics, but their presence was not to be tolerated. The Treasury Department eventually succeeded in closing all of them (Straus 1965). In 1922, the Behrman case determined that it was a crime for a physician to prescribe narcotics to an addict, regardless of the intentions of the prescribing physician (Lindesmith 1965). However, provisions were made for specified institutions to use narcotics in a graded reduction of dose. Shortly after the Behrman case, Dr. Charles 0. Linder prescribed four tablets of a narcotic to an informer who was an addict. Dr. Linder was arrested and convicted. However, about two years after losing his medical license and $30,000 (1920 dollars), he was exonerated by the Supreme Court in 1925. The reversal of the decision in this case recognized addicts as being diseased and proper subjects for medical treatment (Lindesmith 1965). However, the 1925 Linder decision was too little too JourNJI of Psychoactive Drwgs
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tenance treatment (MMT) program physicians who feel that doses of 80-100 mg are massive and dangerous. There was no reference to the use of methadone as a treatment for morphine abstinence (which apparently came a short time later) nor was there mention of oral methadone. In my experience, oral methadone and intravenous (IV) methadone are, acutely at least, two different drugs. Given orally, methadone is subject to extensive first-pass extraction by the liver where it is stored unchanged for later release. When given intravenously, being highly lipophilic, methadone behaves more like heroin. This acute difference diminishes with time. One can only wonder if Isbell and colleagues would have reached different conclusions had they used oral methadone in their 140- to 180-day studies. Oral methadone was established as a treatment for the opioid abstinence syndrome in U.S. Public Health Service hospitals by 1950 (Maddux 1989). The discovery of methadone's unique pharmacokinetic properties did not occur until 14 years later. Meanwhile, on the postwar legislative front, the Boggs Bill was passed in 1951 and later the Narcotic Drug Control Act of 1956. These were efforts to facilitate arrests and convictions, while providing for harsher penalties for those involved with narcotics. In the 1960s, this climate reflected that organized medicine continued to be withdrawn from involvement in the treatment of addiction. There was residual fear among physicians to become involved and there was little motivation to do so. This aversion or lack of interest may be attributed to the total change in the perceived image and character of the contemporary opioid-dependent person as a criminal in contrast to the benign acceptance of the nineteenth century opium eater. I began working with street heroin addicts in the early 1960s and quickly learned not to discuss this activity with my colleagues. Illicit traffic in opioids was thriving, the heroin epidemic was in full swing, and the middle-class junkie had emerged. It was simple to decide where to send a patient for hospital care. All women and men east of the Mississippi River went to the U.S. Public Health Service hospital in Lexington, Kentucky; men west of the Mississippi went to a similar federal hospital in Fort Worth, Texas. In a feature article (Hentoff 1965) in the New Yorker, Dr. Marie Nyswander stated that "the present situation is so damn senseless and tragic. Wait- someone put it more accurately: 'The American narcotics problem is an artificial tragedy with real victims.'" By the late 19 50s and early 1960s, it was clear, at least to some people, that the prohibition model was not working. The conventional treatment of detoxification and discharge was not working. It is no wonder that interest in pharmacological/medical maintenance treatments was revived and enhanced, even though these treatments had been completely dismissed by law enforcement agencies and considered improper by Jourrwl of Psychoactiv~ Drwgs
the medical establishment. In November 1963, Dr. Vincent Dole was awarded a research grant from the New York City Health Research Council (Waldorf 1973). It is very likely that anyone else would not have succeeded, but Dole was a well-established research scientist with the best of credentials and reputation. Also, he had the courage to withstand the pressures of the powerful U.S. Bureau of Narcotics. For example, when told by an agent that he was breaking the law and that they would put him out of business, he invited them to take him to court so that a proper ruling on the matter could be made (Courtwright, Joseph & DesJarlais 1989). The following year, MMT was discovered. Most of the accounts of the events surrounding this discovery are in general agreement. A meaningful account of the early days was provided by Dr. Mary Jeanne Kreek at an informal gathering of some members of the American Society of Addiction Medicine Methadone Treatment Committee in Miami on February 3, 1989. She had been there when history was being made. Back in 1964, Vince, Marie, and I wanted to be absolutely sure that reports from Lexington, Britain, and elsewhere were indeed reproducible in our hands and correct. That is, if you used morphine (we used morphine and not heroin) to treat addiction, even if you used four doses per day, taking into account what was thought to be the pharmacokinetic profile, and mind you, we couldn't measure blood levels of morphine or methadone back then, one could not achieve a steady state. We tried to see if we could stabilize patients on a given dose of morphine, and, the answer, as it had been in everyone else's hands, from the early days of Lexington onward, that increasing doses of morphine had to be administered. We then turned to a drug for which there were indicaton, primarily from pain research plus some short-term detox experience, that suggested it might be longer acting, again not proven pharmacokinetically, and that was methadone, and it had the second advantage of being orally effective. We raised people up to a dose ... what we found, and found it within the first three or four weeks, but really saw it in the first six months to a year, you could bring a person up to a dose that was an adequate treatment dose . .. and level them off at that dose and they would not need any more. They would not need any more to prevent abstinence symptoms at the end of a dosing interval which was soon determined to be 24 houn, and they would not need any more to prevent craving. We then found that patients, one year, two yean, three yean, and four yean still didn't need any more. By that time good critics were saying, "Maybe you have rehabilitated those people so well that it is not even needed any more ... which was a very good question. So on a blinded basis, first single then double, we would reduce people ... and reduce their dose down very slowly to a certain point that we would watch their symptomatology. We found that most people did not have any problem until they got to a certain point, and when we would fmally break the code it would be something between 15 and 35 mg. At that point they would become symptomatic at the end of the 24-hour dosing interval. If we tried to go further than that then the symptoms could be seen at every subsequent dose lowering. We stopped there, and when we would go back up over their critical threshold, which was quite individualized, they would be fme. Sometimes we would have up and down and up and down on a double-blinded basis and not 105
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and also due to a lot of poorly qualified but eager or opportunistic people anxious to solve thenarcotics problem by handing out methadone. "That's when things became disorderly," Dole remarked. 3. Dole made the point that effective rapid expansion could occur with medical competence. He gave the example of Dr. Robert Newman bringing in 20,000 new patients in an efficient, orderly manner with good data collection by a staff that enjoyed excellent morale. 4. The situation led to what Dole called the "regulatory counterattack" that occurred around 1973. The federal government saw the invitation and chose to "reenter the field in a vigorous way, to take command of the whole business and to set up regulations that ... have to a large extent damaged the programs today." Others, especially clinicians using methadone treatment, continue to operate under the restrictions and busywork that resulted from this unprecedented intrusion into the practice of medicine. 5. Along with a lack of understanding of methadone maintenance treatment and opioid addiction some saw methadone as an expedient means to engage people in treatment and to retain them long enough to cure the underlying problems through psychotherapy, prayer or whatever, at whi ch time methadone could be discontinued . Dole referred to this as a kind of hybrid thinking. This thinking was adopted by the regulators who then missed the very basis for methadone maintenance and in the process of regulation by political and ideological compromise turned it all upside down to make abstinence, not rehabilitation, the goal of treatment. The early rapid expansion of methadone maintenance was tolerated by the public mostly for its prospect as areduction in crime. I have often wondered how it might have been if methadone had been publicized as a benefit only to the addict, with no direct benefit to society in the reduction of crime. In the 1970s, public and governmental concerns shifted to the economy. Funded programs ceased to expand, and many faced funding reductions. One of the programs I was involved with at that time was forced to return over 100 addicts to the streets. As might be expected, the ones that were the easiest to treat and who made the program look good were retained, while the sicker and more complicated patients were the flfst to be terminated. At that point in my career I withdrew from the public sector to my private practice, where I hoped to be shielded from the effects of mood swings on the part of the funding powers. As the government reduced its involvement in and commitment to the treatment business, private enterprise moved in. The quality of care provided among this pro-
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break the code, just say 10 the pharmacist; up or down, and the pharmacist at Rockefeller would go up or down accordingly. 'This showed us that, in fact, they still needed methadone, that they were still very dependent on it in terms of prevention of absti nence and craving, but that the full treatment dose that they were on probably wasn't essential to prevent the craving and the ab stinence; however each person would have their own threshold. That showed us that it still was doing something, it wasn't that they had recovered to the point that they no longer had any need for the pharmacologic agent.
Other accounts of the discovery emphasize the dramatic change in behavior. During the two months of attempted morphine maintenance, receiving up to 600 mg parenterally daily, the two patient-subjects were described as being very passive, just waiting patiently for the next injection. With the substitution of 150-180 mg methadone daily by mouth, the patients became active, interested, engaged in purposeful activity. Unger (1985) wondered whether the "invention" of methadone maintenance would have occurred if those first few patients had not been motivated to make some changes. The first two became six, then 22, and by October 1968, 1,139 were in the program. In August 1965, Dole and Nyswander gave a cautious and restrained report of the clinical trials with the first22 patients. The response by the media was not so cautious and restrained, which probably helped excite the critics of any form of medical maintenance treatment. The controversy was born and lives to this day. It would be more accurate to describe the present-day debate as philosophical and ideological differences rather than a true controversy, which is defined as a disputation over a matter of opinion. Today the safety, effectiveness, and value of properly applied MMT is no more controversial than is the assertion that the earth is round . Nevertheless, there was heated philosophical debate during which clinical experience and the derived scientific data were ignored. This phenomenon prompted Newman ( 1977) to write a chapter titled "The Irrelevance of Success" in his book about MMT. The following outline traces the attitudes of the federal government toward methadone maintenance; it draws heavily on Dole's taped interview that appeared in the methadone maintenance section of Addicts Who Survived: An Oral History of Narcotic Use in America,l923-1965 (Courtwright, Joseph & DesJarlais 1989). 1. The early results were most encouraging. Dole described this period from 1965 to 1970 as the honeymoon stage. This was in spite of the continued presence of the U.S. Bureau of Narcotics and other agencies who "carped, infiltrated, and attempted to discredit the program . ... " 2. The early 1970s saw a rapid expansion of methadone maintenance, which was due partly in response to pressures from the Nixon White House Journal of Psychoactive Drugs
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no one knows much about the quality of many programs throughout the country. Work is now under way to define elements of quality in programs, to establish performancebased standards of care, and to develop an MMT quality assurance system. It is very likely that significant changes will occur in MMT in the 1990s. The need is both substantial and urgent, but history has shown the folly of expanding service beyond the capacity to staff programs with competent, well-trained people. There is potential to do a great deal of good or a great deal of harm . It is the responsibility of physicians, psychologists, nurses, counselors, and administrators to be informed and involved in this process to ensure the best possible treatment of the addict-patient toward a goal of full rehabilitation. It is no longer sufficient to take care of patients. Treatment providers must also become teachers, public relations workers, politicians, and advocates for all patients who want and need treatment.
liferation of programs could be described as uneven. Some less than ideal programs seemed to attract a great deal of attention, while some very excellent programs quietly went about their business maintaining a low profile. For whatever reasons, methadone maintenance treatment to this day continues to have an image problem. In the midst of a new wave of acceptance, this time based on the relationship between AIDS and IV heroin use and the clearly demonstrated effectiveness of methadone maintenance in reducing the spread of AIDS (Cooper 1989), it appears that MMT has survived a difficult period of growth and maturation to now experience the process of increasing legitimization (Zweben & Payte 1990). However, that process is quite fragile. While there are many excellent programs, others are lacking quite severely. That MMT is potentially both effective and safe is no longer in question. However, Ball and colleagues ( 1988) have shown that marked differences exist in the effectiveness of various programs. It is probably true that
REFERENCES Ball, J.C.; Lange, W.R. ; Myen, C .P. & Friedman, S.R. 1988. Reducing the risk of AIDS through methadone maintenance treatment JoUI'NJ) of Health and Social Behavior Vol. 29 : 214-226. Black, J.R. 1889. Advantages of substituting the morphia habit for the incurably alcoholic. CinciMati La11cet-Ciinic Vol. 22: 537-541. Cooper, J.R. 1989. Methadone treatment and acquired inununodeficiency syndrome. Journal of the Amuica11 Medical Associatio11 Vol. 262(12): 1664-1668. Courtwright, D.; Joseph, H. & DesJarlais, D. 1989. Addicts Who Survived : A11 Oral History ofNarcotic Use in America,J923-1965. Knoxville: University of Tennessee Press. Dole, V.P. & Nyswander, M. 1965. A medical treatment for diacetylmorphine (heroin) addiction - a clinical trial with methadone hydrochloride. Jowrnal of the America11 Medical Associatio11 Vol. 193(8): 646-650. Hentoff, N. 1965. Profiles: The treatment of patients-! : Dr. Marie Nyswander. New Yorlru July: 32-75. Inciardi, J.A. 1984. The War 011 Drugs: Heroi11, Cocaine, Crime and Public Policy. Palo Alto, California: Mayfield. Isbell, H.; Wikler, A.; Eddy, N.B. ; Wibon, J.L. & Moran, C .F. 1947. Tolerance and addiction liability of 6-dimethylam.i.no-4-4-diphenylheptanon-3 (methadon). Journal of the America11 Medical
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Associatio11 Vol. 135: 888-894.
Lenz, G.R; Evans, S.M.; Walters, D.E. & Hopfmger, A.J. 1986. Opiates. New York: Academic Press. Lindesmith, A.R. 1968. Addictio11 and Opiates. Chicago: A!dine. Lindesmith, A.R. 1965. The Addict and the Law. Bloomington: Indiana University Press. Maddux, J.F. 1989. Personal communication, April. Department of Psychiatry, University of Texas Health Science Center, San Antonio; former director, U.S. Public Health Service Hospital, Ft. Wonh, Texas. Newman, R.G. 19TI. Methadone Treatmefll in Narcotic Addictio11. New York: Academic Press. Straus, N., ill. 1965. Treatmefll Before Cure . New York : Nathan Straus
m. Unger, K.B. 1985. Methadone in the treatment of heroin addictioncurrent state of the an. Califorllia Society for the Treatme11t of Alcoholism and Other Drug Dependencies News Vol. 12(1). Waldorf, D. 1973. Careers i11 Dope. Englewood Cliffs, New Jersey: Prentice-Hall. Zweben, J.E. & Payte, J.T. 1990. Methadone maintenance in the treat· ment of opioid dependence- a current perspective. Wester11 Jountal of Medicine Vol. 152(5): 588-599.
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