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Chemical Dependency Research Working Group |
Methadone maintenance treatment has been thoroughly researched and carefully evaluated for almost three decades. It has received more scientific scrutiny and evaluation than any other medical treatment or human service program (Ball and Ross, 1991; Brecher, 1972; Caplehorn and Bell, 1991; Des Jarlais, Joseph, Dole and Schmeidler, 1983; Dole and Joseph, 1978; Dole and Nyswander, 1976; GAO, 1990; Gearing and Schweitzer, 1974; Inciardi, 1988; Joseph and Dole, 1970; Simpson, 1981; Stimmel, Goldberg, Cohen and Rotkopfe, 1978). Most evaluations have shown that, when correctly implemented, the treatment is capable of producing remarkable improvements in patients who were previously dysfunctional heroin addicts. Methadone maintenance patients throughout the world have been restored to productive lives, relations with families and children have been reestablished, many have furthered their educations, obtained employment and improved their physical and mental health. Nevertheless, contrary to scientific evidence, methadone maintenance treatment remains a controversial issue among substance abuse treatment providers, public officials and policy makers, the public at large and the medical profession itself.
Methadone was synthesized in Germany during World War II as a substitute for morphine when supplies of opium from Turkey were cut off by the United States and their allies. The drug was brought to this country after the war and studied in 1946 at the United States Public Health Hospital in Lexington, Kentucky. It was found to be similar in its effects to morphine but possibly longer acting. Clinical research showed that the drug could be used effectively in the treatment of the opiate abstinence syndrome by substituting it for morphine and slowly tapering down the dose over a period of about one week to ten days (Brecher, 1972). Until the development of methadone as a maintenance medication in 1964, the primary use of methadone in the treatment of addiction was to withdraw addicts from heroin, a procedure that differs from maintenance and exploits only a few of the potentially useful properties of the medication.
By the late 1960s in New York City, heroin related mortality was the leading cause of death for young adults between the ages of 15 and 35 (Joseph and Dole, 1970). Serum hepatitis cases related to injection of narcotics with contaminated needles were increasing. A record number of addicts were being arrested for drug-related crimes, including possession, sales, robbery and burglary, and overcrowded jail facilities with no medical care to ease withdrawal were creating havoc (Inciardi, 1988; Joseph and Dole, 1970). By 1968, the Manhattan County Jail for Men (known as the Tombs) was wracked by riots because of the severe overcrowding and lack of medical care for arrested addicts. With the medical and legal professions calling for a reevaluation of American narcotic policies in respect to treating addicts, the climate was more favorable to challenge the Bureau of Narcotics' anti-maintenance position.
In 1962, Dr. Vincet P. Dole, a specialist in metabolism at the Rockefeller University was appointed to look into the situation by Dr. Lewis Thomas, chair of the Narcotics Committee of the Health Research Council of New York City. After studying the scientific, public health and social ramifications of the addiction problem in the city, Dr. Dole received a grant from the Health Research Council to establish a research unit at the Rockefeller University to investigate the feasibility of opiate maintenance.
In preparing for his research he read the book, The Drug Addict As A Patient by Dr. Marie E. Nyswander (1956), a psychiatrist who had extensive experience treating addicts. She had served as a physician at the U.S. Public Health Service Hospital in Lexington, Kentucky, treated addicts in private psychiatric practice, established a store front for treating addicts in East Harlem and was the psychiatrist for the Musicians Clinic, a program which treated addicted musicians (Hentoff, 1969). Nyswander was convinced addicts could be treated as patients within general medical practice. However, she believed that many would have to be maintained on narcotics in order to function, since the majority relapsed despite many hospitalizations, withdrawal and therapy (Brecher, 1972; Courtwright, Joseph and Des Jarlais, 1989). Nyswander joined Dr. Dole's research staff in 1964. At the same time, a young clinical investigator, Dr. Mary Jeanne Kreek, completing her training in internal medicine and neuroendocrinology at the New York Hospital-Cornell Medical Center, was also recruited to join the research team.
Maintenance with low doses of morphine was administered to the first two patients who had used narcotics for at least eight years and had extensive criminal histories related to their additions (Brecher, 1972; Dole and Nyswander, 1967). Both had previously attempted therapy and had withdrawn from heroin several times, only to relapse. Since morphine has a half life of four to six hours, the patients required injections at least four times per day. As tolerance developed to the morphine, they required increasing amounts administered at more frequent intervals to remain comfortable. And they remained preoccupied with drugs, apathetic and sedated from the narcotizing effects of the morphine.
The researchers knew that morphine's effects are similar to heroin. It was not a good choice as a maintenance drug. While criminal behavior might be reduced because the drug would be obtained legally, the patient would remain dysfunctional. Impairment would result from morphine's narcotizing qualities and the short half life of the drug requiring several injections per day. With the development of tolerance increasing amounts would be needed to remain comfortable over a short period of time. Similar results were obtained for other short-acting narcotics such as hydromorphone, codeine, oxycodone and meriperidine (Dole, 1988 and 1980; Dole, Nyswander and Kreek, 1966). A distinct disadvantage of most of the short-acting narcotics was that to be maximally effective they had to be injected. As Dole (1995) remarked:
"... I could see why Butler had a problem with morpine maintenance, he was using the wrong drug. His intentions were right but you cannot proceed with morphine or heroin. These drugs have too short an action to provide stability of function."
With the failure of short-acting narcotics to properly maintain patients, they were to be withdrawn from morphine using methadone. The same tests that were administered to patients while maintained on morphine were given while the patients were administered methadone. Initially, methadone was injected but because of skin irritation at the site of injection, the mode of administration was changed to the oral route. It was in the course of undergoing metabolic tests of the effects of methadone that the serendipitous discovery of methadone's ideal properties as a maintenance medication occurred. "A fortunate accident" as Dole described the discovery in a lecture at the Beth Israel Medical Center on February 3, 1995. Methadone was already being widely used clinically to withdraw addicts from heroin and research had begun into its use as an analgesic in the experimental treatment of pain (Dole, 1988; Joseph and Dole, 1970; Kreek, 1973). In 1964, the technology was not yet available to measure the blood levels of heroin, morphine and methadone (Borg, Ho and Kreek, 1992). The results concerning the outcome of methadone as a maintenance medication depended on the observations and insights of the researchers. The research team deducted from the consistent successful outcomes of the first methadone patients that continued addiction was a metabolic disease (e.g., the relief of drug craving, the blockade effect created by the development of tolerance, the stability of medication levels, the changes of behavior from preoccupation with drugs to more productive activities such as the desire for work or further schooling, the clarity of affect, the absence of narcotization).
The Eight Important Findings That Distinguish
Methadone as a Preferred Maintenance Drug
Once methadone was established as a proper maintenance medication at doses of 80 to 120 mg/day, eight important findings were noted from clinical research. These findings would constitute the basis of a maintenance program capable of permitting otherwise intractable addicts to function normally within society (Dole, 1988 and 1980; Dole, Nyswander and Kreek, 1966; Kreek, 1978 and 1973; Payte and Khuri, 1992).
In conclusion, methadone when prescribed as a maintenance medication functions as a normalizer for a deranged physiology and not as a mood altering narcotic substitute. It is a corrective but not curative procedure (Dole, Nyswander and Kreek, 1966; Joseph and Dole, 1970).
Admissions Protocols
Initially the criteria for admission to methadone conformed to the needs of a strict research protocol (Brecher, 1972; Gearing and Schweitzer, 1974; Joseph and Dole, 1970). Only addicts between the ages of 21 and 40 were admitted. The upper age limit was based on the theory that addicts begin to mature out of addiction over the age of 40. The applicants had to be addicted to heroin for at least four years and have relapsed after previous attempts at withdrawal from heroin and treatment. Addicts who were polysubstance users, including alcoholics and those afflicted with major psychiatric and medical problems such as tuberculosis, were not considered eligible. Initially women of child bearing age and pregnant addicts were not permitted because the effects of methadone on the reproductive system were not known and the researchers were investigating a new medical procedure (Joseph and Dole, 1970). As methadone treatment proved to be successful and medically safe, the admission criteria were gradually modified.
Today, the regulations of the Food and Drug Administration (FDA) allow heroin addicts to be admitted with a oe year addiction history including current use (Office of the Federal Register, 1993). The lower age limit has been reduced to 16, however applicants between the ages of 16 and 18 must have two prior episodes of either withdrawal from heroin or drug free treatment and parental consent or be declared emancipated before being admitted. The upper age limit has been eliminated since it is now believed that while a group of addicts do mature out, the majority do not. It has subsequently been learned that untreated addicts may have high death rates at young ages, may be incarcerated or become seriously alcoholic (Dole and Joseph, 1978; Joseph and Appel, 1985). Women of child bearing age and pregnant women are now accepted and, with special medical justification, a pregnant woman can be admitted with an addiction history of slightly less than one year. Applicants with major medical conditions and polysubstance abuse problems including alcoholism are now eligible for treatment (FDA, 1989).
Methadone Maintenance Expands:
The Gearing Study and Subsequent Evaluations
In 1965, under the guidance of Dr. Ray Trussell, the New York City Commissioner of Hospitals, the initial research project was expanded and transferred to the Manhattan General Hospital in New York City where a heroin withdrawal program had previously been established. An impartial unit to evaluate the expansion and progress of methadone treatment was created at the Columbia University School of Public Health and Administrative Medicine with Dr. Frances Rowe Gearing as the chief of evaluation. The unit's work was reviewed by an independent committee composed of physicians and scientists with Dr. Henry Brill as its chairman. The committee made recommendations for further evaluation, research and expansion of the program (Joseph and Dole, 1970). Thus, methadone maintenance received rigorous scrutiny and evaluations with follow-up studies that continue to this day.
No matter what country, ethnicity, sex, education or economic background of the patients, studies evaluating methadone have been consistent. The following summarizes the findings from major studies conducted over the past approximate three decades.
Studies by Ball and Ross (1991) and McLellan and colleagues (1993) demonstrates the need for psychosocial services in methadone programs to ensure their maximum potential in helping patients. In the 1980s and 1990s, new admissions presented serious social, psychological and medical problems to clinics. Among the problems are homelessness, cocaine/crack addiction, alcoholism, HIV infection, drug resistant tuberculosis, mental illness, chronic unemployment, poor education and a host of social problems (Joseph, 1992; Joseph and Appel, 1993).
In an important study, McLellan and colleagues (1993) have shown that while methadone alone is effective for some patients, the addition of services results in better treatment outcomes for a greaternumber of patients. All patients in the study were maintained at 60 mgs/day or more of methadone and dose was increased as needed if use of opiates persisted. Patients were assigned to one of three service components: (1) Minimal care included an adequate dose of methadone but no other services. (2) Standard care included an adequate dose of methadone plus counselling. (3) Enhanced services included an adequate dose of methadone plus counseling, on-site medical/psychiatric/employment services and family therapy.
The study found that patients involved in enhanced program services showed significant improvements in social adjustment and employment status, with significant decreases in alcohol and cocaine use and illegal activity. McLellan also reported that when dysfunctional patients receiving minimal care were given standard care, the improvements in reduction of illicit opiate and cocaine use were significant and occurred rapidly within a period of four weeks. Patients receiving enhanced care in the McLellan study made significantly greater improvements than those receiving standard or minimal care.
A study of socially productive methadone patients (employed, in school or homemakers) by shows that patients are able to hold positions across the spectrum of the job market (Joseph and Des Jarlais, 1980) . To qualify for an interview in this study, patients had to be in treatment for at least four years, not involved with illicit drugs or criminality for at least three years, and be employed outside the field of drug treatment, drug-related research or drug-related social services. Furthermore, they had to have addiction histories of four or more years.
A Review of Methadone Treatment: Outcome and Follow-up Studies
Some major follow-up studies of discharged methadone patients in the United States and Europe have found that a large majority are unable to maintain abstinence and eventually relapse to daily heroin use. Despite the fact that many of these studies were conducted prior to the homelessness, AIDS and crack/cocaine epidemics, they are remarkably consistent across ethnic, racial and cultural differences. These studies are important since they show that the majority of discharged patients were unable to make sustained good posttreatment adjustments in a less threatening era. The studies include those by Ball and Ross, 1991; Caplehorn, 1994; Cushman, 1980; Des Jarlais, Joseph, Dole and Schmeidler, 1983; Dole and Joseph, 1978; Dole and Nyswander, 1976; Gearing and Schweitzer, 1974; Gunne, Gronbladh and Ohlund, 1993; Joseph and Dole, 1970; Simpson, 1981; and Stimmel, Goldberg, Cohen et al, 1978.
The overwhelming evidence is that the majority of patients who leave methadone maintenance, irrespective of their type of discharge (favorable vs. unfavorable) and their individual prospects for successful abstinence, eventually relapse to daily use of narcotics (Caplehorn, McNeil and Kleinbaum, 1993). Today, persons who are HIV negative and leave methadone treatment are at high risk of contracting the virus after leaving treatment because of the high rate of relapse to drug use.
Neuroscience Developments During the Post World War II Era
The development of methadone maintenance occurred during a period of revolutionary research in the field of neurobiology. This research helped to reconceptualize theories of addiction involving biological factors as a predominant factor for protracted addictive behavior. Prior to World War II, the physical basis of an addiction was hypothesized and alluded to by researchers and clinicians. However, as previously described in this study, the knowledge base was lacking to give credence to this line of thought. The seminal breakthroughs that would ultimately transform thinking about the action of drugs in the post World War II period could be briefly summarized as follows:
The continuing ongoing research in laboratories worldwide to further unravel this system including the very specific and elusive drug craving that appears to generate a prolonged opiate addiction.
Conclusion
The work of Dole and Nyswander has had a great impact on the treatment of heroin addicts in the United States today. First, they brought the treatment and care of addicts into the medical profession, albeit a controlled isolated and highly regulated clinical system. Nevertheless, this was an incredible accomplishment in itself, considering the lack of understanding and resistance to the concept that a continuing opiate addiction had a strong underlying metabolic component. However, it must be emphasized that methadone maintenance did not expand because society wanted to provide treatment for heroin addicts. To the contrary, the main concern was reducing the number of crimes committed by addicts.
Their second accomplishment, although they did not realize it at the time, was the launching of the first and most ffective harm reduction program. Harm reduction takes a public health approach toward the problem of drug use with pragmatic strategies to reduce the harm that drugs do to the individual and society. The emphasis on drug enforcement and punishment as the primary strategies to control drug use is replaced with education, prevention and treatment. Today the program has been expanded and is the major public health program for the treatment of heroin addiction in the United States. Presently, there are about 115,000 persons known to be enrolled in approximately 750 methadone maintenance treatment programs in 40 states.
The third impact is in the field of neurobiology. Dole's conceptualization of opioid receptor cells, their density, location within the brain and laboratory techniques necessary to discover them has opened up a vast field of research which is ongoing to the present day. Dole was presented with the Lasker Award for Medical Clinical Research in 1988 because of these two accomplishments: the development of methadone maintenance and the conceptualization of opioid receptor sites.
Commentary
As a comment to this chapter, methadone in the form of dolophine tablets was prescribed informally by private physicians as a possible withdrawal procedure or short term maintenance therapy for opiate addiction. However, the procedures were never researched, conceptualized or developed into a coherent theoretical framework. The physicians were usually harassed by the Bureau of Narcotics and threatened with a revocation of their medical licenses. "Jerry," one of the narrators in the book, Addicts Who Survived, used dolophine prescribed by a physician when he was unable to obtain opium. He entered methadone treatment in 1973. Dolophine in the 1950s and 1960s was called "dollies" by street addicts and was used for self medication. They were obtained from physicians or through the forging of prescriptions (Courtwright, Joseph and Des Jarlais, 1989).
An informal methadone maintenance program using dolophine was organized by the New York State Department of Mental Health in 1959 under the direction of Dr. Harold Meiselas.1 Meiselas acknowledged that coherent research protocols and evaluations were never organized (Meiselas, 1995). Furthermore there were no conceptualizations of dose leading to the establishment of narcotic blockade. Formal records are now lost nor are there records of patient outcomes and papers about the experience were never written. However, Meiselas did recall that addicts were initially given methadone in a hospital on Ward's Island in a building owned by the state but which was subsequently turned over to a therapeutic community.
After an unknown period of hospitalization the patients received methadone in the community in outpatient clinics that were operated by the Deartment of Mental Hygiene. Administrative arrangements and permission to proceed with this pilot were made by Dr. Henry Brill.2 There were about 30 patients enrolled in the program. Meiselas advised that there are to his knowledge no existing records of how this project began or ended. However, he believes that some of the patients may have entered the Dole-Nyswander program that was established in the 1960s. He does recall having meetings about the program and that methadone was chosen for the program since it was a long acting drug.
The above shows the importance of conceptualization in research and the importance of evaluation. Prior to Dole's work, physicians who may have used methadone did not appreciate the pharmacology of it nor did they develop concepts to further their work. Their basic understanding of addiction was that of a behavioral problem and methadone was merely a long acting substitute for heroin. In contrast, Dole approached addiction as a metabolic disorder and believed that addicts could be treated in the physician's office like any other patient with a chronic disease. In addition to bringing the addict back under the care of physicians, Dole imparted the importance of research, conceptualization and evaluation. Dole's work resulted in a system that generated knowledge and ongoing study but most importantly, the knowledge produced a sound medical protocol that can be implemented worldwide.
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Last Update: March 15, 2001 |
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