Historical Perspectives and Public Health Issues

i. Introduction

The use of methadone maintenance to treat addiction to heroin and other opiates was developed in the mid-1960s and has become the most widely employed treatment of opiate dependence in the United States. Consistent with its origins as an intervention to curb heroin addiction, methadone maintenance treatment now has another public health role to play: helping curtail the spread of HIV among opiate-dependent IDUs.

Methadone was synthesized in Germany during World War II as an analgesic alternative to morphine. The drug was first studied in this country in 1946 at the U.S. Public Health Hospital in Lexington, Kentucky, after the war. Methadone was found to be similar to morphine in its effects but possibly longer acting. The drug could be used effectively to treat opiate withdrawal syndrome by substituting methadone for morphine and slowly tapering the dose over a period of about 7-10 days, as shown by clinical research.

Before methadone maintenance treatment was developed in 1964, methadone was used primarily in the treatment of addiction to withdraw addicts from heroin, a short-term procedure that exploits only some of methadone's potentially useful properties. Methadone maintenance treatment, on the other hand, involves administering a constant, therapeutic daily dose of methadone after an initial period of buildup or stabilization, concomitantly with medical, rehabilitation, and counseling services.

This treatment regimen, when correctly implemented and adhered to, can produce dramatic improvements in individuals who were formerly dysfunctional addicts. In clinics throughout the world, methadone maintenance treatment patients have been restored to productive lives. Many have furthered their education, obtained training and employment, resumed or established careers and businesses, improved their physical and mental well-being, and renewed family relationships. Nevertheless, the treatment regimen remains a source of contention among substance abuse treatment providers, public officials and policymakers, the public, and the substance abuse treatment profession itself, despite more than two decades of research and evaluation that internationally document its safety and efficacy.

The next section discusses the historical background of opiate dependence in the United States and how conflicting attitudes toward opiate maintenance treatment existed prior to the development of methadone maintenance. These attitudes continue to influence policy toward the modality despite scientific evidence that it is safe and effective. The chapter concludes with a discussion of some issues of concern, such as methadone's medical safety, its role in treating opioid-dependent, pregnant women, and its role as a public health intervention to prevent the spread of HIV.

I. Historical Perspectives

During the past century, historical, political, and social forces shaped the nature of opiate dependency in the United States. Opiate dependency has occurred in a variety of groups at different times, suggesting that the availability of narcotics and personal biological vulnerability, as opposed to a unique set of social or personality characteristics, cause narcotic dependence. A variety of social or personality characteristics may influence the expression of an addictive disorder, but historical evidence rules against the concept of these characteristics being at the root of addiction.

To illustrate this point, older white women from the middle and upper socioeconomic classes constituted about two-thirds of those addicted to opiates (morphine sulfate and laudanum) during the late 19th century. Narcotics were widely prescribed to alleviate acute and chronic discomfort and stress, which resulted in iatrogenic addiction. There were an estimated 300,000 opiate- dependent persons in the United States by 1900. The prototype iatrogenic, white, female addict of this particular era was the mother of playwright Eugene O'Neill, Mary Tyrone, portrayed in the autobiographical drama, "Long Day's Journey Into Night." Another group medically addicted to narcotics in the late 19th century were disabled and wounded veterans of the Civil War (Courtwright 1982; Courtwright et al. 1989).

Iatrogenic addiction among middle and upper class older white women and disabled war veterans was regarded as an unfortunate medical condition and thus elicited tolerance and empathy. Neither group presented major social problems. Doctors prescribed narcotics to these groups, and sanatoria were established for questionable "cures" of the resulting opiate addiction. However, the chronic nature of addiction was evident, as many of the patients who entered the sanatoria for the cure relapsed after discharge. In the above-mentioned play, the addictive qualities of morphine and the high relapse rate were known to Eugene O'Neill's father, which contributed to his refusal to send his wife to a sanatorium. Addicted Civil War veterans and elderly white women were dying by the end of the century, and doctors became more cautious in prescribing narcotics to their patients. Eventually the prevalence and incidence of addiction diminished in these two groups.

The arrival of waves of European immigrants at the turn of the century changed the composition of the addicted population. Impoverished young adults, crowded into tenements and ghettos, became susceptible to addiction. Use of opium, cocaine, and heroin and drug-related crime were sources of concern to social, religious, and political leaders in poor, urban communities.

In the decades after World War II, another major change in the opiate- dependent population occurred. There was a mass migration of African-Americans from rural areas and cities in the southern United States and Hispanics from Puerto Rico, the Caribbean Islands, and Central and South America to northern and western cities during this period. As European immigrants moved out of the crowded cities, Hispanics and African-Americans moved into the vacated tenements in areas with preexisting problems of narcotics addiction and trafficking. An ethnic succession of narcotics addicts occurred in these neighborhoods, with African-Americans and Hispanics replacing those of white European background (Courtwright 1982; Courtwright et al. 1989).

A corresponding change in attitudes toward addicts also occurred--from compassion and support for the iatrogenically addicted, older, white females and disabled Civil War veterans to discrimination and stigmatization of poor white, Chinese, African-American, and Hispanic addicts in the inner-city ghettos. This stigmatization of addicts and their drugs of abuse reflected class and ethnic biases within the community, and this culturally biased perspective was extended to methadone after it was introduced as a medical maintenance medication in the 1960s.

These attitudes have found expression in over eight decades of restrictive Federal legislation and local statutes beginning with the passage of the Harrison Narcotic Act of 1914 (Courtwright et al. 1989). This act was passed by Congress to fulfill U.S. obligations to uphold the international agreement of the 1912 Hague Convention to help curtail the opium trade in southeast Asia and China. Although mercantile and trade interests of the United States were also at stake, the transformation of American addicts to a white criminal underclass and a Chinese minority in the first decades of the century was used as a rationale for enacting the statute (Brecher 1972; Courtwright 1982; Courtwright et al. 1989).

The Harrison Act was not originally constructed as a prohibition law but as a measure to regulate the manufacture, distribution, and prescription of opiates, coca, and their derivatives. Manufacturers, pharmacists, and physicians had to be licensed, keep records for inspection, and pay a modest fee to the Internal Revenue Bureau of the Treasury Department. The act did not, however, deal directly with the issue of physicians prescribing narcotics to maintain addicts. it and a 1919 amendment allowed physicians to prescribe narcotics for "legitimate medical purposes" in the course "of their professional practice only," but did not define the two phrases. Because the Treasury Department's Narcotics Division took the position that addiction was not a disease and that addicts were not legitimate patients, it followed from their interpretation of the law that physicians who prescribed drugs for maintenance were not prescribing to patients in the course of their professional practices. Thus, the Treasury Department adopted an antimaintenance attitude that eventually resulted in the harassment and imprisonment of doctors who continued to treat addiction by prescribing opiates (Brecher 1972; Courtwright 1982; Courtwright et al. 1989; Gewirtz 1969).

Before the Harrison Act was passed, opiate-dispensing clinics had already been opened in Florida, in 1912, and Tennessee, in 1913. After the antimaintenance decisions of the Supreme Court in 1919, (1) 13 municipalities with large populations of addicts established about 44 opiate clinics in which morphine was prescribed or dispensed to addicts. Some clinics prescribed heroin and cocaine (Courtwright et al. 1989).

Clinics varied in their functions: Some were detoxification programs, and others adopted a maintenance policy (Brecher 1972; Cooper 1988; Courtwright 1982; Courtwright et al. 1989; Gewirtz 1969). Morphine maintenance is not an efficient procedure, however, because of morphine's short duration of action (4 to 6 hours), the increasing tolerance level requiring periodic patient dose increases, the need to inject the drug several times a day and the persistence of incapacitating narcotic effects, such as somnolence (Courtwright et al. 1989; Joseph and Dole 1970). In the period 1912-24, long-acting narcotics such as methadone had not yet been synthesized or conceptualized, and physicians had to use the drugs of the period to address a serious health problem.

Perhaps the most famous clinics were the Department of Health clinic in New York City, where addicts were detoxified with decreasing doses of heroin and morphine, and the clinic established by Dr. Willis Butler in Shreveport, Louisiana. Dr. Butler not only detoxified patients, but also maintained the addicted citizenry on morphine, including, among others, the local sheriff's elderly, infirm mother. The Commissioner of Public Safety objected to the presence of the opiate clinic in Shreveport until he discovered that his own mother was a patient. This example illustrates an important point: The perception of who is addicted influences the attitude toward addiction (Courtwright et al. 1989).

Clinics differed in the way they were administered. Some were well run and kept accurate records, while others were haphazard in their operation; some clinics operated for profit while others were part of a public health policy. Irrespective of their clinical function, administrative status, or effectiveness, the clinics were regarded by the Treasury Department as a threat to its antimaintenance philosophy. A campaign ensued to close the clinics using legal pressure, critical inspections, and threats. By 1923, the Treasury Department succeeded in this undertaking. The last clinic to be closed was the one operated by Dr. Butler in Shreveport (Courtwright 1982; Courtwright et al. 1989).

With the closing of the opiate treatment clinics, there were no governmental programs for the treatment of addiction. Subsequently, an increase in crime associated with the acquisition of narcotics was reported in cities throughout the country. In 1929, Congress appropriated funds to establish a treatment facility, the U.S. Public Health Service Hospital in Lexington, Kentucky, which opened to patients in 1936. This institution detoxified addicts who entered voluntarily and also served as a prison hospital for convicted and sentenced addicts. The prescribed stay in the institution was about 6 months, although some patients stayed longer. While the hospital offered social, medical, psychological, and psychiatric services in addition to detoxification and had a low patient-to-staff ratio (2 to 1), the atmosphere was nevertheless prisonlike. Two major followup studies showed the program to be a failure. One study reported a relapse rate of 93 percent in 1,912 former patients over a 1-to-4.5-year followup period; a second study found a relapse rate of 97 percent in 453 former patients over followup periods of 6 months to 5 years. Because of these failure rates and the subsequent establishment of community-based programs, the hospital facility was turned over to the Bureau of Prisons in 1974 (Brecher 1972; Courtwright et al. 1989).

The increase in heroin addiction in New York City following World War II led to the establishment of Riverside Hospital for adolescent addicts. The hospital, located on North Brothers Island in the East River, had 141 beds and a professional staff of 51. A followup study by Dr. Harold Alksne in 1956 showed that of the 247 patients admitted in 1955, 86 percent had relapsed, 11 percent had died, and only eight former patients (3 percent) were abstinent. Upon further investigation, it was found that the eight patients abstinent at followup were never addicted but were arrested on narcotics charges and chose hospitalization over jail. The facility was closed in 1961 by Dr. Ray Trussell, then Commissioner of the New York City Department of Hospitals (Brecher 1972).

The narrow and punitive interpretation of the Harrison Act by the Federal Narcotics Division led to an era of restrictive narcotics regulation. Harassment, arrests, and convictions of physicians who prescribed narcotic drugs for maintenance were common enough to stand as a warning to the medical profession. Subsequently, addicts were forced to buy drugs on the black market and were subject to street violence, diseases associated with use of unsterilized needles, arrests, convictions, and incarcerations (Brecher 1972). By 1970, Congress had passed 55 antinarcotics laws, and State legislatures had supplemented Federal laws with hundreds of local statutes.

In the 1950s, trends in cities throughout the United States were becoming clear. The number of heroin addicts was increasing, as was addiction-related crime. By the 1980s, there were an estimated 500,000 narcotics users in the country, most located in the inner cities among poor, minority young men and women. While this represented a 66-percent increase over the estimated number of addicts in the late 19th century, the per capita rate of addiction was much less than in the late 19th century because the population had more than doubled (Courtwright et al. 1989). Also, by the 1960s, the composition of the addicted population had changed from white, middle and upper class women and wounded Civil War veterans to poverty-stricken, largely nonwhite people living in the ghettos of major American cities. Addiction became not only a major medical problem but an explosive social issue (Courtwright 1982; Courtwright et -al. 1989).

To allay fears of addiction related crimes against property in the inner cities, civil commitment was instituted in California and New York State. Addicts could be committed to facilities through a voluntary procedure that included a medical examination to validate the presence of an addiction or be committed for 3 years when arrested on a misdemeanor charge as an alternative sentence to jail. The civil commitment program instituted in New York in 1966 turned out to be exceedingly expensive; it cost about $156 million per year to commit 5,800 addicts, while the positive results were minimal (Brecher 1971-). The great majority of addicts absconded from aftercare programs to which they were paroled after a period of institutionalization in a State commitment facility and could not be located. A review of the California civil commitment experience showed that five out of every six addicts committed and placed on aftercare in the 1960s either relapsed, were rearrested, absconded, died, or were removed from the program by a writ of habeas corpus (Brecher 1972; lnciardi 1988; Joseph 1988; Joseph and Dole 1970 Maddux 1988).

Both the legal and medical professions in the United States were perturbed by the post-World War II rise in heroin addiction and the serious personal, social, and medical consequences of American policy. In 1956, the joint Committee of the American Bar Association and the American Medical Association was formed to study the problem. In 1958, the committee issued its report recommending that an outpatient facility prescribing narcotics be established on a controlled experimental basis (Brecher 1972).

Other prestigious groups voiced support for the concept of an opiate maintenance clinic. The New York Academy of Medicine recommended in 1955 and again in 1963 that clinics be established in affiliation with hospitals to dispense narcotics to addicts. In 1956, the American Medical Association advocated a research project that would investigate the feasibility of dispensing narcotics within a clinic. In 1963, President Kennedy's Advisory Commission on Narcotic and Drug Abuse also recommended that research be implemented to determine the effectiveness of dispensing narcotics to addicts in outpatient clinics (Brecher 1972). After many years of punitive legislation and policy, support grew for narcotic maintenance, especially because no effective abstinence-based alternative existed to treat the large number of addicts.

II. The Origins of Methadone Maintenance

With the medical and legal professions calling for a reevaluation of American policies concerning the treatment of addicts, the climate was more favorable for a challenge to the Narcotics Division's antimaintenance position. By the mid- and late 1960s, heroin- related mortality was the leading cause of death for young adults between 15 and 35 in New York City. The number of serum hepatitis cases related to injection of opiates with contaminated needles was increasing. Record numbers of addicts were being arrested for drug-related crimes (e.g., possession, sales, robbery, and burglary), and overcrowded jails had no effective medical care available to ease detoxification (Inciardi 1988; Joseph and Dole 1970). By 1968, the Manhattan County Jail for Men (known as the Tombs) was wrecked by riots because of the poor living conditions, severe overcrowding, and lack of medical care for arrested addicts.

In 1962, Dr. Vincent P. Dole, a specialist in metabolism at The Rockefeller University, was appointed chair of the Narcotics Committee of the Health Research Council of New York City by Dr. Lewis Thomas. Dr. Dole received a grant from the Health Research Council to establish a research unit to investigate the feasibility of opiate maintenance after studying the scientific, public health, and social ramifications of the addiction problem in the city. In preparing for his research at The Rockefeller University he read The Heroin Addict as a Patient by Dr. Marie E. Nyswander, 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, and established a storefront for treating addicts in East Harlem; she was also the psychiatrist for the Musicians Clinic, a program which treated addicted musicians. Dr. Nyswander was convinced addicts could be treated as patients within general medical practice. However, she was of the opinion that many, would have to be maintained on narcotics in order to function, since the majority relapsed, notwithstanding detoxifications, hospitalizations, and psychotherapy (Brecher 1972; Courtwright et al. 1989). Dr. Nyswander joined Dr. Dole's research staff in 1964. Also recruited to join the research team was a young clinical investigator, Dr. Mary Jeanne Kreek, who was completing her training in internal medicine and neuroendocrinology at the New York Hospital-Cornell Medical Center.

Maintenance with low doses of morphine was first administered to two patients who had used narcotics for at least 8 years and had extensive criminal histories related to their addictions. Both had previously attempted therapy and had detoxified several times only to relapse. Since morphine has a half-life of 4-6 hours, the patients required injections four times per day. They remained preoccupied with drugs and were apathetic and sedated from the narcotizing effects of morphine. As tolerance to the morphine developed, they required increasing amounts administered at more frequent intervals to remain comfortable.

The researchers knew that morphine, which is related to heroin, was not a good choice as an opiate maintenance medication because the patient's social functioning was impaired by morphine's narcotizing qualities. Also, the short half-life of the drug requires several injections per day and as tolerance develops, increasing amounts are needed over a short time for patients to remain comfortable. Other short-acting narcotics, such as heroin, codeine, oxycodone, and meriperidine, showed similar results (Dole 1980, 1988; Dole et al. 1966).

With short-acting narcotics eliminated as options for maintenance, the research focused on another possible maintenance drug. Methadone appeared to be orally effective and long-acting and was selected on the basis of observations of its use in withdrawing addicts from heroin and as an analgesic in the experimental treatment of pain (Dole 1980,1988; Joseph and Dole 1970; Kreek 1973). However, in 1964 technology was not available to measure blood levels of heroin, morphine, and methadone to assess duration of action. At that time, proof of the efficacy of methadone maintenance treatment was dependent on observation and recognition by insightful researchers.

Methadone was then administered to the patients who had first been maintained on morphine. Once tolerance to a dose of 80-120 mg/ day was established, it was noted that patients were able to function normally without the anxiety associated with drug craving. During the research phase of methadone maintenance treatment, the following six important findings about methadone were noted; they support a maintenance program's ability to permit otherwise intractable addicts to function normally in a socially acceptable manner (Dole 1980,1988; Kreek 1973).

• The patients did not experience euphoric, tranquilizing, or analgesic effects. Their affect and consciousness were normal. Thus, they were able to socialize and work normally without the incapacitating properties of short-acting narcotics like morphine or heroin (Dole 1980, 1988; Dole et al. 1966; Kreek 1973).
• At a methadone dose between 80 and 120 mg/day, tolerance to the narcotic effects of all opiate- class drugs (e.g., morphine, heroin, Demerol, opium) was held at a level high enough to block their euphoric and tranquilizing effects if the patient administered them by injection or by smoking.
• There was no change in tolerance levels over time; therefore, the dose could be held constant indefinitely (e.g., over 20 years) (Dole 1980,1988; Kreek l973).
• Methadone was effective when administered orally, and because it has a half-life of 24-36 hours, it could be taken by patients once per day without the use of injection needles (Dole 1980, 1988; Dole et al. 1966; Kreek 1973).
• Most importantly, methadone relieved the narcotic craving or hunger described by addicts as a major factor in relapse and continued illegal heroin use (Dole 1980,1988; Dole et al. 1966; Kreek 1973).
• Finally, the research indicated that methadone was medically safe and nontoxic (Kreek 1973, 1978). Methadone, like most opiate-class drugs, might cause minimal side effects. These effects would be experienced with greater frequency at the beginning of treatment and included constipation, excessive sweating, and decreased libido. Sweating appeared to be the most persistent effect. Constipation could be treated with diet or hydrophilic colloid and usually subsided. Libido usually returned to normal during the first months of treatment for the majority of patients; if not, an adjustment of the methadone dose could help to correct this particular complaint, although sexual problems, such as decrease in libido, were also associated with alcoholism, polysubstance abuse, or advancing age. While on methadone maintenance, female patients who may have had amenorrhea while addicted to heroin usually experienced normal menses.

III. The Expansion of Methadone Maintenance: From Research Project to Public Health Program

In 1965, under the guidance of Dr. Ray Trussell, Commissioner of the New York City Department of Hospitals, the initial research project on methadone safety and efficacy was expanded and transferred to the Manhattan General Hospital in New York City where a heroin detoxification program had previously been established. An impartial unit to evaluate the expansion and progress of methadone maintenance 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 Columbia University unit's work was reviewed by an independent committee composed of physicians and scientists chaired by Dr. Henry Brill. The committee recommended further evaluation, research, and expansion of the program (Joseph and Dole 1970).

In general, Gearing found that patients' social functioning improved with time in treatment as measured by decreases in and eventual elimination of heroin use and increased employment, school attendance, and homemaker status. Most patients were stabilized on 80-120 mg/ day of methadone. Except for attempts by most new patients to "test the blockade," patients who remained in treatment curtailed and subsequently eliminated heroin use. However, about 20 percent or more of the patients entered treatment with serious alcohol and polysubstance abuse despite intake screening (Gearing and Schweitzer 1974). Treatment was continued for these patients when their conditions were discovered, and attempts were made to treat the alcoholism and polysubstance abuse.

The successful outcomes led to expansion of the program so that methadone maintenance became the major public health initiative for the treatment of heroin addiction. By 1992, approximately 115,000 patients were enrolled nationwide in methadone maintenance treatment programs.

IV. Federal Leadership

(2)While Drs. Dole, Nyswander, Kreek, Lowinson, Gearing, Goldstein, Brill and others were continuing to understand the mechanisms of action and the therapeutic impact of methadone maintenance, events within the Federal government were occurring that would result in the rapid expansion of this treatment modality. In early 1970, the domestic advisors to President Nixon became concerned with the increasing evidence of heroin addiction's relationship to crime on the streets. The White House staff began to visit local treatment programs to examine the treatment programs that were available. Those they visited were all located within large metropolitan areas and had major components that were providing addiction treatment services using methadone maintenance. They were particularly impressed with the programs developed in the District of Columbia under the leadership of Dr. Robert DuPont.

The White House staff then commissioned two groups to provide policy and program recommendations for initiatives to respond to the increasing heroin addiction. One group was led by staff of the National Institute on Mental Health (NIMH) with collaboration from staff from the Office of Economic Opportunity (OEO), DEA, and the Department of Housing and Urban Development (HUD). The other was made up of professionals working in communities as program directors and researchers in drug addiction treatment. Both groups submitted lengthy papers containing their recommendations. The NIMH-led group recommended that methadone not be approved as a treatment, but that it should be subjected to further research. The nongovernmental advisory group espoused a strategy that would rapidly expand all forms of treatment and would extensively employ methadone maintenance.

This recommendation became Federal policy in June 1971 when the President named Dr. Jerome Jaffe as the Director of the Special Action Office for Drug Abuse Prevention (SAODAP). One of Dr. Jaffe's early goals was to promulgate FDA regulations that would govern the use of methadone to treat opioid addiction.

Prior to this policy decision, NIMH had been the focus of concern with researching and evaluating addiction treatment, During the late 1960s, NIMH provided support to the National Association for the Prevention of Addiction to Narcotics (NAPAN) as a cosponsor of the annual conferences concerning methadone maintenance. Additionally, Dr. Sidney Cohen, the Director of the Division of Narcotic Addiction and Drug Abuse at NIMH, obtained Investigational New Drug (IND) approval from FDA for methadone maintenance treatment. Under this IND, patient data were collected from all NIMH-funded treatment programs that chose to use methadone.

However, the use of a drug under an IND linked methadone treatment to a research status that could easily be revoked if policymakers so decided. Further, while the IND permitted investigators to study agents that were not fully approved by FDA as safe and efficacious, there were no provisions for dealing with "investigators" who deviated from the proposed "protocols." During the late 1960s and early 1970s, there were a number of so-called investigators who chose to supply methadone to heroin addicts in large quantities with virtually no other services or monitoring. The behavior of the "investigators," motivated primarily by profits they made from charging addicts for treatment, led to considerable diversion of methadone: Two such investigators, one in Washington, D.C. and one in New York City, were particularly egregious, and their persistence demonstrated the inability of the IND model to limit the modality to legitimate practitioners.

At the same time, it became obvious that FDA was reluctant to grant approval to a treatment that had not followed the usual procedures of carrying out carefully structured double-blind studies on safety that met the requirements that FDA required of the pharmaceutical industry. Thus, on the one hand, it was obvious that the idea of methadone as "research" was no longer appropriate, because methadone benefited the patients and appeared to be safe; on the other hand, it would not be appropriate to approve methadone as an ordinary medication like a new antibiotic. Some new approach was needed that could make treatment available to heroin users who could benefit, but would allow government to prevent exploitation by unscrupulous practitioners.

Thus the first regulations were proposed in the early 1970s by FDA, with input from DEA, NIMH, and OEO, although they were never promulgated. These regulations were carefully crafted and were so restrictive that criticisms from within the Department of Health, Education and Welfare (DHEW), as well as from other levels of government, caused the regulations to be withdrawn. Later, with the advent of SAODAP, Dr. Jaffe, as the Director of that office, was able to insist that an acceptable set of regulations be published.

From that point on, even though the funding policies of the Federal government were modality neutral, many people accused the Federal government of being promethadone. However, analyses of the funding of drug programs by Federal agencies demonstrated that nonmethadone outpatient programs were more numerous than methadone maintenance programs and that Federal support for nonmethadone programs far exceeded that for methadone programs.

In the early 1970s, under the auspices of SAODAP, special monographs were published that set forth the recommended treatment regimen for methadone maintenance. These monographs attempted to place a greater emphasis on treatment and rehabilitation services than did the FDA regulations. The issues addressed included patient-counselor ratios, richness of service mix, urine screening, and dosage recommendations. Regrettably, these issues remain unresolved today despite 20 years of research and clinical experience to guide our patient care.

In 1974, Congress legislated a role for DEA in regulating methadone clinics. In 1980, NIDA and FDA formed an agreement to jointly develop and issue the methadone maintenance treatment regulations. Several modifications were made to the regulations during the 1980s as a result of information developed through extensive clinical care experience and research data uncovered by NIDA- funded investigators.

Also during recent years, reports by GAO, testimony by the Director of NIDA, and papers published by NIDA scientists and scientists working in other countries have all confirmed the safety, efficacy, and clinical benefit of methadone maintenance as an essential element in the spectrum of treatments for opioid addiction.

Today, with the concerns for the spread of the AIDS virus, treatment modalities that result in the reduction of high-risk behaviors, such as needle use, needle sharing, and the exchange of sex for drugs, are even more desirable. Methadone maintenance has established itself as an effective addiction treatment reducing risk factors related to HIV. This fact has given policy and program personnel additional reasons to consider expanding methadone maintenance treatment for the treatment of opioid dependence.

V. Criteria for Admission to Methadone Maintenance Treatment

Initially, criteria for admission to methadone maintenance treatment conformed to the requirements of a strict research protocol. Only addicts between the ages of 21 and 40 were admitted. The upper age limit was established on the basis of an unconfirmed theory that addicts "mature out" of addiction over age 40. Applicants had to be addicted to heroin for at least 4 years and had to have relapsed after previous attempts at treatment and detoxification. Addicts who were polysubstance abusers or alcoholics, and those with major psychiatric problems and medical problems such as TB, were not considered eligible. Initially, pregnant opioid- dependent patients were not admitted because this was an investigation of a new medical procedure (Joseph and Appel 1985; Joseph and Dole 1970). The admission criteria were gradually modified to include previously excluded groups as methadone maintenance treatment proved successful and medically safe. Dr. Kreek's work was central to establishing the medical safety of methadone maintenance for all groups of patients.

Today, the FDA/NIDA regulations allow heroin addicts to be admitted with a 1-year addiction history including current physical dependence. The minimum age has been lowered to 18; however, applicants between 16 and 18 may be admitted if they have two prior attempts at detoxification or nonmethadone maintenance treatment and have parental consent or are declared emancipated before being admitted. The upper age limit has been removed since there are elderly addicts who have not "matured out" of addiction. Results of followup studies have shown that untreated addicts have high death rates, continue to use drugs after the age of 40, may be incarcerated, or may become seriously alcohol-dependent (Dole and Joseph 1978; Joseph and Appel 1985). Pregnant opioid-dependent women are now accepted and, with special medical justification, can be admitted under modified criteria (e.g., past history of addiction with current risk of readdiction, addicted to narcotics for less than 1 year but using at time of application). Applicants with major medical conditions and polysubstance abuse problems including alcoholism are also now eligible for treatment (Dole and Joseph 1978; FDA 1989; Joseph and Appel 1985; Gearing and Schweitzer 1974).

VI. Treatment of Opiate Addiction as a Metabolic Disease

In the 1960s, researchers at The Rockefeller University began to question prevailing theories of addiction that were predicated on psychological attributes of addicted persons and conditioning theory. Dole and Nyswander (1967) indicated in an article addressing these ideas that heroin addiction may be a metabolic disease. Clinical and laboratory studies suggest that the relapse- provoking narcotic hunger is symptomatic of a metabolic dysfunction within the endogenous opiate receptor-ligand system that results from repeated use of opiates.

Although some patients function normally without medication after a period of treatment, the majority experience a return of drug hunger. If they do not reenter treatment, they are likely to relapse despite being motivated to remain abstinent and to attempt to function normally within the community. Therefore, methadone maintenance treatment is a corrective, not a curative, procedure of indefinite duration (Dole 1988; Kreek 1973, 1976).

Kreek studied subjects who detoxified from heroin or methadone and who succeeded in remaining abstinent from narcotics. She observed that during abstinence there are persistent abnormal neuroendocrine effects in both groups and has speculated that these abnormal responses in neuroendocrine functioning can contribute to relapse (Kreek 1986, 1988). With new analytic techniques available and the discovery of the specific ligands that bind to receptors, Dole supports the renewed interest in the study of the protracted abstinence syndrome (AS) (Kreek 1973,1986).

VII. Methadone Dose

As previously indicated, a blockade to the narcotic effects of all opiate- class drugs is achieved when methadone is prescribed within the range of 80-120 mg/ day. This phenomenon was tested during the initial research by Dole, Nyswander, and Kreek at The Rockefeller University in a double-blind study. Patients were challenged for 4 weeks with heroin, morphine, Dilaudid, methadone, and a saline blank at different levels of stabilization and stages of narcotic tolerance. For patients maintained on 80-100 mg/day of methadone, the euphoric effects of all opiate-class drugs were abolished or inconsequential. The blockade was effective for the amount of heroin in several illegal bags that an addict would be able to purchase on the streets (Dole et al. 1966).

The public health implications of these findings were not apparent until large-scale studies were completed over long periods. These studies subsequently showed that patients maintained on doses of 70 mg/day or more made better adjustments than those maintained on lower doses. Hartel and coworkers (1988) analyzed about 190,000 urine toxicology reports for 2,400 methadone patients enrolled in an MMTP in the South Bronx over a 15-year period (1972- 88). A trend line was discovered at the 70 mg/day level that held for the entire period: Those patients maintained on 70 mg/day or more stayed in treatment longer, used less heroin and other drugs, including cocaine, and had a lower incidence of AIDS and HIV infection. The effectiveness of methadone was more pronounced for patients maintained at 80 mg/day, especially for protection against HIV infection.

A series of research studies emerged that supported the concept of a therapeutic effective dose range:

• A comprehensive study by Ball and Ross of six MMTPs in Baltimore, New York City, and Philadelphia showed that patients reduced their use of IV heroin by 71 percent compared with their preadmission level (Ball and Ross 1991). A study of IV heroin use of 407 patients over a period of 1 month showed that the higher the methadone dose, the lower the frequency of heroin use. About 27.9 percent of the 204 patients receiving 45 mg/day or less used heroin, while only 5.4 percent of the 203 patients maintained on doses greater than 45 mg/day did so. However, for those patients maintained on doses of 75 mg/day, no evidence of heroin use was found.
• In a review of 44 methadone maintenance programs, Watters and Price found that the level of dose was the single most important factor related to retention in treatment (the higher the dose, the longer patients stayed in treatment) (Appel unpublished).
• Caplehorn and Bell showed that retention in Australian programs increased by a factor of about two across each of three stratified levels of dose (<60 mg/day, 60-79 mg/day, and 80+ mg/day). Those patients stabilized at a blockade level of 80+ mg/ day had longer periods of treatment than other patients. In this study, variables usually associated with good patient outcomes, such as employment status, educational level, and degree of criminality, appeared to have less of an impact than the patient's dose of methadone (Caplehorn and Bell 1991).
• In a review of the literature, Hargreaves indicated that patients appear to do better on higher doses in the range of 50 to 100 mg/day, especially at the beginning of treatment, and recommended that NIDA encourage State agencies to allow local programs to prescribe methadone up to a dose level of at least 100 mg/ day (Hargreaves 1983).
• In a nationwide study of 172 randomly selected methadone maintenance treatment programs with a 72 percent response rate, D'Aunno and Vaughan found that about half of the programs encouraged patients to detoxify from methadone within 6 months after treatment admission. Sixty- eight percent of the programs set an upper limit for methadone doses at 50 mg/day, which is below the therapeutic effective dose recommended by GAO. As in other studies, the researchers found that patients maintained on higher doses of methadone remained in treatment longer. When patients participated in decisions related to dose and flexible take-home privileges, positive outcomes were more likely (longer duration of treatment and less illicit substance abuse). They recommended monitoring and, in certain cases, changing treatment practices of programs prescribing inadequate doses with minimal patient participation in decision making. Programs treating high percentages of African-American patients, younger populations, and the unemployed appeared to have lower dose limits for patients, administered lower doses of methadone (on the average), may have encouraged patients to detoxify prematurely, and had less patient participation in decisions than other units (D'Aunno and Vaughan 1992).

VIII. Methadone Maintenance Treatment and the AIDS Epidemic

Injecting and noninjecting drug users, their sexual partners, and their offspring are at high risk for contracting HIV. The prevalence of HIV infection among patients entering methadone maintenance treatment varies depending on the program and its geographic location (Joseph and Springer 1990).

Several independent studies have shown that successful methadone maintenance treatment reduces risk behavior to contract and transmit HIV. Abdul-Quader and coworkers (1987) have reported that both the frequency of injection and the frequency of injection in shooting galleries were significantly reduced with time in methadone maintenance treatment. Studies from Uppsala, Sweden, and the South Bronx in New York City (Blix and Grondbladh 1988; Hartel et al. 1988) showed that patients who entered methadone maintenance treatment before 1983 and continued in treatment had significantly lower rates of AIDS and HIV infection than patients who entered after 1983. Both studies suggested that methadone maintenance treatment may be associated with a reduced risk of contracting HIV and may offer protection to IDUs who are not yet infected.

Weber and coworkers (1990) conducted a 3-year prospective study in Switzerland that followed a group of HIV-infected methadone-maintained patients and a contrast group of HIV- infected heroin users who did not enter methadone maintenance treatment. The results showed that the progression of HIV to AIDS was slower among the methadone- maintained patients than among the untreated heroin users. A significantly lower proportion of methadone- maintained patients progressed to AIDS compared with the untreated heroin users within the period of the study (24 percent versus 41 percent).

A study of 58 socially rehabilitated long-term methadone maintenance patients (employed, not using drugs, socially stable) showed that all were seronegative for antibody to HIV, but 91 percent had one or more markers of hepatitis B infection. These patients were enrolled in methadone maintenance treatment for approximately 16.9 years and were maintained on a median dose of 60 mg/day (range 5 to 100 mg/day). Prior to entering methadone maintenance treatment, individual patients had injected heroin for an average of 10.3 years and engaged in high- risk behaviors for contracting HIV (e.g., sharing needles, shooting drugs in shooting galleries, having sexual contacts with other substance abusers). Successful outcomes during methadone maintenance treatment in this group of patients were associated with an absence of HIV infection (Novick et al. 1990).

IX. Medical Safety

Methadone Maintenance and the Immune System

Methadone doses administered for maintenance treatment or pain do not affect the functioning of the immune system. This fact is important to consider when treating HIV- infected patients. Untreated heroin addicts exhibit symptoms of compromised immune function similar to those observed in patients infected with HIV, such as reduced effectiveness of natural killer (NK) cells, enlargement of lymph nodes, and higher absolute numbers of CD cells. However, Kreek demonstrated in a study of 34 heroin addicts that the low levels of NK activity returned to normal in 53 percent of the subjects when placed on methadone (Kreek 1988).

In a study of parenteral heroin addicts, socially rehabilitated long-term methadone maintenance patients, and healthy nonaddicted controls, it was found that NK activity was significantly reduced among the heroin users. However, NK activity in the methadone- maintained patient and control groups did not differ. Also, the heroin users had absolute higher numbers of CD2, CD3, CD4, and CD8 positive cells than the patients and the controls (Novick et al. 1989). In an in vitro study of human peripheral mononuclear cells incubated with a wide concentration of methadone, it was found that NK activity was not affected by methadone concentrations in the plasma of maintained patients and patients under therapy for management of pain (Ochshorn et al. 1990). These studies appear to indicate that abnormalities of cellular immunity found among parenteral heroin users can be normalized when heroin users are placed on adequate doses of methadone, thereby strengthening the immune system response to infections such as HIV.

Methadone Maintenance and Pregnancy

It is important that pregnant heroin users be placed in treatment during the first trimester of pregnancy. Because heroin is a short-acting drug with a half-life of 4-6 hours, the fetus may be subjected to periodic daily episodes of withdrawal resulting in fetal stress and possible intrauterine death. Because of its long-acting duration, methadone, when prescribed in adequate doses, provides a relatively nonstressful environment in which the fetus can develop throughout pregnancy.

Entrance into methadone maintenance treatment during the first trimester of pregnancy is also associated with higher infant birth weights. There is evidence that methadone maintenance treatment, combined with prenatal services, may promote fetal growth, while continued use of heroin during pregnancy may result in infant morbidity (Kaltenbach and Finnegan 1992). However, the pregnant methadone-maintained patient may experience withdrawal symptoms and need an increase in the daily dose of the medication because of changes in metabolism and blood plasma levels of methadone, especially in the third trimester.

Kaltenbach and Finnegan have shown that there is no correlation between maternal dose of methadone, gestational age of neonate, weight in grams, and severity of the neonatal abstinence syndrome (AS). The neonatal syndrome may persist in phases of varying intensity during the first month after birth but can be successfully treated with paregoric. If the mother uses a variety of nonopiate drugs including alcohol, then phenobarbital, in addition to paregoric, may alleviate infant distress (Kaltenbach and Finnegan 1992).

Kaltenbach and Finnegan conclude that methadone does not impair the physical, emotional, or cognitive development of newborns when provided to pregnant substance abusers within an integrated program that addresses the mother's polysubstance abuse, medical, psychological, and social problems. Methadone maintenance treatment in pregnancy also contributes to the reduction of morbidity and mortality rates for both the mother and child (Kaltenbach and Finnegan 1992).

Medical Complications and Medical Safety

Kreek has demonstrated that methadone prescribed in high doses has no toxic effects and minimal side effects. Medical complications identified among methadone- maintained patients include chronic illness that existed prior to treatment or coexisting medical problems and conditions, such as chronic alcoholism, polysubstance abuse (cocaine and other drugs), HIV infection, and AIDS. Other conditions prevalent at time of admission to treatment include chronic liver disease, TB, and syphilis. Patients may also suffer from various forms of trauma and malnutrition. The effects of chronic alcoholism (e.g., cirrhosis and other liver disease) are a major medical problem among patients.

The patientÕs health may be poor at the time of admission to methadone maintenance treatment. However, for those who remain in treatment, health status generally improves unless the patients have AIDS, cancer, and other illnesses with high mortality rates. There are few contraindications for treating methadone maintenance patients with serious conditions. However, methadone maintenance patients treated with rifampin for TB may experience withdrawal symptoms and need to be maintained on higher doses of methadone or prescribed an alternate medication for the treatment of TB. Also, patients cannot be treated with drugs classified as antagonists (such as naloxone) or analgesics that combine agonist/antagonist properties (such as Talwin). Using these drugs will precipitate withdrawal symptoms.

Since 1986, the number of cases of multidrug-resistant TB associated with homelessness and HIV infection has increased. Subsequently, TB has emerged as a major public health problem within methadone maintenance programs. Many clinics now dispense medications for the treatment of AIDS (e.g., AZT) and TB and provide treatment for alcoholism and cocaine addiction in addition to dispensing methadone. Admissions of women, many of whom are pregnant and in ill health, have also increased. Many programs are now developing special initiatives for pregnant women to ensure they are enrolled in prenatal care.

X. Other Concerns

Employment

In the 1960s and early 1970s, many of the patients were still able to obtain well-paying blue collar jobs. The Federal Rehabilitation Act of 1973 and parallel State human rights laws protected individuals in methadone maintenance treatment from employment discrimination solely on the basis of their past drug record and participation in treatment. The right of individuals in MMTPs to hold jobs, even safety-sensitive jobs, has been upheld in several cases under the Rehabilitation Act (Davis v. Bucher 1978; Doe v. New York City Transit Authority 1987).

Protection against discrimination under the Rehabiltation Act and the more recent Americans with Disabilities Act is very important because the Supreme Court had held in Beazer v. New York City Transit Authority (1978) that excluding methadone-maintained individuals from all jobs within the Transit Authority did not violate equal protection under the constitution. In this ruling, the Supreme Court overturned two lower court decisions that had found that individuals maintained on methadone should not be excluded from all jobs. Unfortunately, scientific research documenting that methadone-maintained patients can function without impairment was either ignored or not fully understood. However, the statutory protections of the Rehabilitation Act and the Americans with Disabilities Act make the Beazer decision virtually irrelevant.

Nevertheless, with the change to service-sector employment during the past decade, it has become increasingly difficult to place patients without the required education and skills in jobs that pay well. Furthermore, employment opportunities for many patients have been reduced by the economic recessions of the past decade, and the employment rate for methadone maintenance patients has declined in inner cities. To help patients obtain employment in a changing job market, vocational assessment and counseling have become important social components of treatment. Homelessness has also affected a number of patients, especially those living in inner-city ghettos. Patients who have refused to go to shelters have been found sleeping in subways and other public places. Counselors have, therefore, assumed responsibility for helping homeless patients to obtain living quarters through referrals to community agencies.

Social Stigma

Unfortunately, the general public and some professionals have disparaged and trivialized methadone maintenance treatment as "just substituting one drug for another." These attitudes negatively affect programs in many ways, but it is the methadone maintenance patients themselves who are most stigmatized and harmed, irrespective of what they have accomplished. Therefore, they remain hidden, ashamed of being enrolled in a program that has helped them, and fearful of social ostracism and loss of employment. According to Cooper (1992), misunderstandings about disease of addiction, the role of methadone maintenance treatment, and the stigma associated with the program may underlie counterproductive practices within the program, such as prescribing lower than effective doses of methadone. To dispel myths and misunderstandings about the use of methadone in the treatment of heroin addiction, it is important that the public, professionals, and the patients themselves be educated, and that outreach programs be developed for untreated addicts.

XI. Summary

Heroin injection and its sequelae, both personal and social, generate many of the major public health and social problems facing the United States today. As in past epidemics, effectively treating the infected individual and the individual at risk are prime concerns of public health policy. Methadone maintenance treatment has the potential to achieve both goals by treating narcotics addicts who compulsively use drugs, perpetuate illicit drug use, and act as vectors for the transmission of HIV, STDs, TB, hepatitis, and other infectious diseases.

Effective methadone maintenance treatment has the potential to remove individuals from trajectories that support destructive behavior. This modality also has the potential to provide the necessary pharmacological, psychological, and social supports to help individuals improve their lives. If methadone maintenance treatment is to reach its potential, outreach and educational programs, the development of need-related services, and evaluation are necessary.

The major public health strategy for methadone maintenance programs is to develop flexible intake procedures to admit without delay the large number of untreated addicts who need and apply for treatment and to ensure that relevant services are available to meet their needs. These goals challenge policymakers as well as health and social service workers. Neglecting problems that face many untreated heroin addicts and methadone maintenance patients affects, and will continue to affect, the quality of life in the United States.

Endnotes

1. The Treasury Department's antimaintenance position was upheld in two cases before the Supreme Court in 1919; Webb et al. v. United States and United States v. Doremus. Two subsequent cases repudiated the Webb decision (Lindner v. United States (1925) and Boyd v. United States (1926); however, the Narcotics Division of the Prohibition Unit of the Treasury Department chose to adopt the antimaintenance position as set forth in the Doremus and Webb decisions.
2. This section on Federal leadership was prepared by Karst J. Besteman, Director and Principal Investigator, Institutes for Behavioral Resources, Inc., Substance Abuse Center, Washington, D.C.

References

Abdul-Quader, A.S.; Friedman, S.R.; Des Jarlais, D.C.; Marmor, M.M.; Masiansky, R.; and Bartelme, S. Methadone maintenance and behavior by intravenous drug users that can transmit HIV. Contemporary Drug Problems (Fall 1987):425-433, 1987.

Appel, P. Treatment issue report #56: Review of a NIDA grant. The relationship of treatment policy to client retention, by Watters, J.A., and Price, R.H. Bureau of Research and Evaluation, University of Michigan. Unpublished internal report of the New York State Division of Substance Abuse Services.

Ball, J.C., and Ross, A. The Effectiveness of Methadone Maintenance Treatment. New York: Springer-Verlag, 1991.

Beazer v. New York City Transit Authority, 440 U.S. 568 (1978).

Blix, O., and Grondbladh, L. AIDS and IV heroin addicts: The preventive effect of methadone maintenance in Sweden. Abstract 8548. Fourth International Conference on AIDS, Stockholm, Sweden, 1988.

Brecher, E.M. Licit and illicit drugs. In: Consumers Union Report on Narcotics, Stimulants, Depressants, Inhalants, Hallucinogens, and Marijuana. Boston, MA: Little, Brown and Company, 1972.

Caplehorn, J.R.M., and Bell, J. Methadone dosage and retention of patients in maintenance treatment. Medical Journal of Australia 154(February 4):195-199,1991.

Cooper, J.R. Methadone treatment in the United States. In: Awni, A., and Westmermeyer, J., eds. Methadone in the Management of Opioid Dependence: Programs and Policies Around the World. Geneva, Switzerland: World Health Organization, 1988.

Cooper, J.R. Ineffective use of psychoactive drugs: Methadone treatment is no exception. Journal of the American Medical Association 267(2):281-282, 1992.

Courtwright, D.T. Dark Paradise: Opiate Addiction in America Before 1940. Cambridge, MA: Harvard University Press, 1982.

Courtwright, D.T.; Joseph, H.; and Des Jarlais, D. Addicts Who Survived: An Oral History of Narcotic Use in America, 1923-1965. Knoxville, TN: University of Tennessee Press, 1989.

D'Aunno, T., and Vaughn, T.E. Variations in methadone treatment practices. Journal of the American Medical Association 267(2):253-258, 1992.

Davis v. Bucher, 451 F., supp. 791 (E.D.Pa. 1978).

Doe v. New York City Transit Authority, 85 Civ. 4521 (S.D.N.Y. 1987) (Consent Degree).

Dole, V.P. Addictive behavior. Scientific American 243(6)(December):138- 154,1980.

Dole, V.P. Implications of methadone maintenance for theories of narcotic addiction. Journal of the American Medical Association 260(20) (November 25):3025-3029,1988.

Dole, V.P., and Joseph, H. Long-term outcome of patients treated with methadone maintenance. Annals of the New York Academy of Sciences 311:181-189, 1978.

Dole, V.P., and Nyswander, M.E. Heroin addiction: Metabolic disease. Archives of Internal Medicine 120:19-24, 1967.

Dole, V.P.; Nyswander, M.E.; and Kreek, M.J. Narcotic blockade. Archives of Internal Medicine 118(October):304-309, 1966.

Food and Drug Administration. FDA Regulations in the Federal Register. 21 CFR Part 21. Washington, DC: Food and Drug Administration, March 2,1989.

Gearing, F.R., and Schweitzer, M.D. An epidemiologic evaluation of long- term methadone maintenance treatment for heroin addiction. American Journal of Epidemiology 100:101- 112,1974.

Gewirtz, P.D. Notes and comments: Methadone maintenance for heroin addicts. The Yale Law Journal 78:1175-1211, 1969.

Hargreaves, W.A. Methadone dose and duration for maintenance treatment. In: Research on the Treatment of Narcotic Addiction: State of the Art. National Institute on Drug Abuse Research Monograph. DHHS Pub. No. (ADM)97-1281. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1983. pp. 19-92.

Hartel, D.; Selwyn, P.A.; and Schoenbaum, E.E. et al. Methadone maintenance treatment and reduced risk of AIDS and AIDS-specific mortality in intravenous drug users. Abstract No. 8546. Fourth International Conference on AIDS, Stockholm, Sweden, June 1988.

Inciardi, J.A. Some considerations in the clinical efficacy of compulsory treatment: Reviewing the New York experience. In: Compulsory Treatment of Drug Abuse: Research and Clinical Practice. National Institute on Drug Abuse Research Monograph 86.1988.pp. 126-138.

Joseph, H. The criminal justice system and opiate addiction: A historical perspective. In: Compulsory Treatment of Drug Abuse: Research and Clinical Practice. National Institute on Drug Abuse Research Monograph 86.1988. pp. 106-125.

Joseph, H., and Appel, P. Alcoholism and methadone treatment: Consequences for the patient and the program. American Journal of Drug and Alcohol Issues 11(1,2):37-53, 1985.

Joseph, H., and Dole, V.P. Methadone patients on probation and parole. In: Federal Probation June 1970. pp. 42-48.

Joseph, H., and Springer, E. Methadone maintenance treatment and the AIDS epidemic. In: The Effectiveness of Drug Abuse Treatment: Dutch and American Perspectives. Malabar, FL: Robert E. Krueger, 1990. pp. 261-274.

Kaltenbach, K., and Finnegan, L.P. Methadone maintenance during pregnancy: Implication for perinatal and developmental outcome. In: T. Sonderegger, ed. Perinatal Substance Abuse: Research Findings and Clinical Implications. Baltimore: Johns Hopkins University Press, 1992.

Kreek, M.J. Medical safety and side effects of methadone in tolerant individuals. Journal of the American Medical Association 223(6): 1973.

Kreek, M.J. Medical complications in methadone patients. Annals of the New York Academy of Sciences 311(Dept. 29):110-134,1978.

Kreek, M.J. Tolerance and dependence: Implications for the pharmacological treatment of addiction. In: Harris, L.S., ed. Problems of Drug Dependence (Proceedings of the 48th Annual Scientific Meeting of the Committee on Problems of Drug Dependence). DHHS Pub. No. (ADM)87-1508. Rockville, MD: National Institute on Drug Abuse, U.S. Department of Health and Human Services, 1986. pp. 53-62.

Kreek, M.J. Summary of presentation at 1988 meeting of the Committee for Problems of Drug Dependence. NIDA Notes Fall: 12, 25,1988.

Kreek, M.J. Multiple drug abuse patterns and medical consequences. In: Meltzer, H.Y., ed. Psychopharmacology: Third Generation of Progress. New York: Raven Press. pp. 1597-1904.

Maddux, J.F. Clinical experience with civil commitment. In: Compulsory Treatment of Drug Abuse: Research and Clinical Practice. National Institute on Drug Abuse Research Monograph 86.1988. pp. 35-56.

Novick, D.M.; Joseph, H.; and Croxson, T.S. et al. Absence of antibody to human immunodeficiency virus in long-term, socially rehabilitated methadone maintenance patients. Archives of Internal Medicine 15O(January):97-99, 1990.

Novick, D.M.; Ochshorn, M.; and Ghali, V. et al. Natural killer activity and lymphocyte subsets in parental heroin abusers and long-term methadone maintenance patients. Journal of Pharmacology and Experimental Therapeutics 250:606-610, 1989.

Ochshorn, M.; Novick, D.M., and Kreek, M.J. In vitro studies of the effect of methadone on natural killer cell activity. Israel Journal of Medical Sciences 26(8):421-425, August 1990.

Weber, R.; Ledergerber, B.; Opravil, M.; and Luthy, R. Cessation of intravenous drug use reduces progression of HIV infection in HIV+ drug users. Abstract of the Sixth International Conference on AIDS, San Francisco, June 1990.

For Further Reading

(Back)

Ball, J.C., and Ross, A. The Effectiveness of Methadone Maintenance Treatment. New York: Springer-Verlag, 1991.

Brecher, E.M. Licit and Illicit Drugs. Boston: Little Brown and Company, 1972.

Committee for the Substance Abuse Coverage Study, Division of Health Care Services, Institute of Medicine. Treating Drug Problems. Vol. 1. Gerstein, D.R., and Harwood, H.J., eds. Washington, DC: National Academy, Press, 1990.

Courtwright, D.T.; Joseph, H.; and Des Jarlais, D. Addicts Who Survived: An Oral History of Narcotic Use in America, 1923-1965. Knoxville, TN: University of Tennessee Press, 1989.

Dole, V.P. Addictive behavior. Scientific American 243(6):138-154,1980.

Dole, V.P. Methadone maintenance from a public health perspective. April 30, 1989. Report available from Dr. Dole, The Rockefeller University, New York City.

General Accounting Office Report. Methadone Maintenance.GAO/HRD-90- 104,1990.

Hartel, D. Cocaine use, inadequate methadone dose increase risk of AIDS for IV drug users in treatment. NIDA Notes 5(l)(Winter), 1989/1990.

Hartel, D.; Schoenbaum, E.E.; and Selwyn, P.A. et al. Temporal patterns of cocaine use and AIDS in intravenous drug users in methadone maintenance. Paper presented at the 5th International Conference on AIDS, Montreal, Canada, June 1989.

Musto, D.F. The American Disease: Origins of Narcotic Control. New York: Oxford University Press, 1987.

National Institute on Drug Abuse. Extent and Adequacy of Insurance Coverage for Substance Abuse Services (Institute of Medicine Report: Treating Drug Problems). Vol. II. Drug Abuse Services Research Series, No. 3. DHHS Pub. No. (ADM)92-1989. Washington, DC: Supt. of Docs., U.S. Govt. Print. Off., 1992.

The Office of Substance Abuse Services. Methadone Position Paper. Lansing, MI, 1990.

Rosenblum, A.; Magura, S.; and Joseph, H. Ambivalence towards methadone treatment among intravenous drug users. Journal of Psychoactive Drugs 23(l):21-27,, 1991.