5
Federal Regulation of Methadone Treatment

The roots of the concurrent regulation of certain drugs under two statutory schemes go back to the beginning of this century. In 1906, Congress enacted the Pure Food and Drug Act, establishing one regime of regulation to assure (among other things) that drugs were not adulterated or misbranded. These regulations were amended several times, recodified in 1938, and expanded on again from the 1940s through the 1990s. Their implementation and enforcement is today assigned to the Food and Drug Administration (FDA) in the Department of Health and Human Services (DHHS).

In 1914, Congress adopted the Harrison Narcotic Act to stop abuse of addictive drugs. The Harrison Narcotic Act was amended in 1937 to include marijuana. In 1965, amphetamines, barbiturates, and hallucinogens came under regulation, but under the Federal Food, Drug, and Cosmetic Act. In 1970, these various statutes were consolidated and recodified as the Controlled Substances Act (CSA), which has been amended several times since then. Its implementation and enforcement is today assigned to the Drug Enforcement Administration (DEA) in the Department of Justice.

In short, two distinct regulatory schemes—one based on truth-in-labeling to protect consumers using drugs for medical purposes, the other based on limiting access altogether to protect the public from drugs of abuse—have grown up in parallel for 80 years. About 75 years ago, and again 25 years ago, the traditions underpinning each scheme came together and conflicted. The issue each time was whether opiate addicts should be given an opiate to "maintain" their addictions.1

1  

"Maintain" here simply means provide methadone for a period longer than the minimum required to detoxify the addict from heroin or opiate use and long enough to wean him or her off methadone itself without greatly debilitating physical symptoms.



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--> 5 Federal Regulation of Methadone Treatment The roots of the concurrent regulation of certain drugs under two statutory schemes go back to the beginning of this century. In 1906, Congress enacted the Pure Food and Drug Act, establishing one regime of regulation to assure (among other things) that drugs were not adulterated or misbranded. These regulations were amended several times, recodified in 1938, and expanded on again from the 1940s through the 1990s. Their implementation and enforcement is today assigned to the Food and Drug Administration (FDA) in the Department of Health and Human Services (DHHS). In 1914, Congress adopted the Harrison Narcotic Act to stop abuse of addictive drugs. The Harrison Narcotic Act was amended in 1937 to include marijuana. In 1965, amphetamines, barbiturates, and hallucinogens came under regulation, but under the Federal Food, Drug, and Cosmetic Act. In 1970, these various statutes were consolidated and recodified as the Controlled Substances Act (CSA), which has been amended several times since then. Its implementation and enforcement is today assigned to the Drug Enforcement Administration (DEA) in the Department of Justice. In short, two distinct regulatory schemes—one based on truth-in-labeling to protect consumers using drugs for medical purposes, the other based on limiting access altogether to protect the public from drugs of abuse—have grown up in parallel for 80 years. About 75 years ago, and again 25 years ago, the traditions underpinning each scheme came together and conflicted. The issue each time was whether opiate addicts should be given an opiate to "maintain" their addictions.1 1   "Maintain" here simply means provide methadone for a period longer than the minimum required to detoxify the addict from heroin or opiate use and long enough to wean him or her off methadone itself without greatly debilitating physical symptoms.

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--> The first clash occurred after World War I, when so-called "morphine clinics" existed and physicians prescribed or dispensed morphine to addicts. Some addicts were veterans of the American Civil War, the Spanish-American War, and WWI, who had become addicted during treatment for war wounds, but most of them came from the growing population of nonmedical addicts (Courtwright, 1982). The Narcotics Division of the Prohibition Unit of the Department of the Treasury, which was then responsible for enforcing the Harrison Narcotic Act, concluded that this activity was not the legitimate practice of medicine but simple drug trafficking. The Treasury Department swiftly closed the clinics and made it personally and professionally risky for physicians to "maintain" a narcotic addict for any reason. In did so, however, only after the American Medical Association had adopted a resolution, in 1920, opposing "ambulatory clinics'' (Musto, 1987, p. 148) This story, as summarized above, became part of the "lore" that affected medical practice and research for almost 50 years and had a profound influence on government officials when the issue of narcotic maintenance again emerged in relation to methadone. In 1972, the public health establishment, including the Secretary of Health, Education, and Welfare, the Food and Drug Administration, the National Institute of Mental Health, and the Special Action Office for Drug Abuse Prevention, was unprepared to allow the Bureau of Narcotics and Dangerous Drugs, DEA's predecessor agency, to unilaterally define the parameters of medical practice for the use of methadone in the treatment of heroin addiction. As a consequence, a new set of rules—the third, on top of the FDA and DEA schemes—was added, one that inserted FDA deeply into the practice of medicine, notwithstanding its protestations to the contrary. Congress ratified this joint responsibility of law enforcement and public health officials for methadone through this third set of rules in 1974 with the passage of the Narcotic Addict Treatment Act (NATA). To examine in detail the evolution of this third set of rules—commonly referred to as the FDA or DHHS methadone regulations—we turn, first, to the period of the mid-1960s. The 1960s Increased use of heroin in the post World War II period first became apparent in the early to mid 1950s. By the end of that decade, New York City had established a special program for young people. The U.S. Public Health Service hospital at Lexington, Kentucky, admitted a number of unemancipated minors from major eastern U.S. metropolitan areas. And during the Eisenhower Administration, a minimum mandatory narcotics law was enacted in 1956, effective July 1957.

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--> In the 1960s, the use of amphetamines and marijuana, in addition to heroin, increased rapidly, especially among younger persons. From the mid-1960s onward, however, concern about heroin use among inner city residents began to displace earlier concern about psychopharmacological drugs of pleasure. The unfolding policy response to these events included a 1962 White House conference on drug abuse, the President's Advisory Committee on Narcotic and Drug Abuse (the Prettyman Committee) of 1963, the Drug Abuse Control Amendments of 1965, the President's Commission on Law Enforcement and Administration of Justice (the Katzenbach Commission) of 1966–1967, and the Narcotic Addiction Rehabilitation Act of 1966. The 1965 Drug Abuse Control Amendments brought under strict federal control all nonnarcotic drugs capable of producing serious psychotoxic effects when abused. This act also created the Bureau of Drug Abuse Control within the Department of Health, Education, and Welfare (DHEW) and shifted the basis for federal law enforcement of illegal drugs from tax principles (administered by the Department of Treasury) to the regulation of commerce (administered by the DHEW). The 1966 Narcotic Addiction Rehabilitation Act (NARA) authorized the civil commitment of narcotic addicts, and federal assistance to state and local governments to develop a local system of drug treatment programs. With respect to the latter, the National Institute of Mental Health (NIMH) initially proposed the gradual implementation of the state assistance effort, mainly through a common mental health mechanism—inpatient treatment programs. However, because of a perceived pressing need, the courts began to commit addicts to these programs even before they were officially opened or staffed. Overwhelmed, most programs were forced to provide less costly services on an outpatient basis, which subsequently became the primary setting for addiction treatment. (Courtwright, 1992; Bestamen, 1992) The NARA legislation imposed the following contract requirements on treatment centers: (1) thrice-a-week counseling sessions; (2) weekly urine tests; (3) restorative dental services; (4) psychological consultations and vocational training; and (5) the treatment modalities of drug-free outpatient, therapeutic community, and methadone maintenance (interview of Karst Besteman by Richard A. Rettig, December 20, 1993; hereafter Besteman interview2). These policy developments were accompanied by changes in the federal agencies responsible for narcotics. Reorganization Plan No. 1 of 1968 transferred the primary functions of the Federal Bureau of Narcotics (FBN) from the Treasury Department to the Department of Justice; it also transferred the DHEW Bureau of Drug Abuse Control functions to the Department of 2   Karst Besteman was deputy director of the NIMH Division of Narcotic Addiction and Drug Abuse in the late 1960s and early 1970s.

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--> Justice. Within the Justice Department, the Bureau of Narcotics and Dangerous Drugs (BNDD) was created, which became the Drug Enforcement Administration in 1973. DHEW responsibilities for narcotic addiction treatment were lodged in the NIMH. The NIMH nucleus eventually became the basis for the National Institute on Drug Abuse. The Nixon Administration Under the first Nixon administration (1969–1972), federal drug abuse policy developed in a significant way. These developments included a 1969 "war on drugs" presidential message, resulting legislation in 1970, and a Special Action Office created by executive order in 1971 and authorized in statute in 1972. The perception that the heroin problem in the United States was an epidemic was reinforced at the end of the 1960s and during the early 1970s by the widespread exposure of GIs in Vietnam to the drug. A fear arose that many GIs, sent to Vietnam often against their will and over the protests of many of their countrymen, would return not as conquering heroes but as heroin addicts. This prospect, plus the public concern with crime and the association of crime and illegal drug use, led President Nixon, in 1969, to send a message to Congress on drug abuse. Although this was the first time that a U.S. president invoked the "war on drugs" image, it was in retrospect the most balanced approach to the problem of drug abuse that had been advanced. Although Nixon's blueprint gave highest priority to supply reduction, it also placed strong emphasis on demand reduction, more so than did any subsequent administration. 1970 Legislation The 1969 message resulted in the submission of legislation to the Congress and the passage, the following year, of the Comprehensive Drug Abuse Prevention and Control Act of 1970 (Public Law 91-513, October 27, 1970). The act dealt with research, treatment, and prevention of drug abuse and drug dependence, and with drug abuse law enforcement authority. One major purpose of the 1970 legislation was to reverse some of the strictures of the Harrison Act of 1914. The 1970 act sought "to clarify for the medical profession . . . the extent to which they may safely go in treating narcotic addicts as patients. There are relatively few practicing physicians in the U.S. today who treat narcotic addicts because of the uncertainty as to the extent to which they may prescribe narcotic drugs for addict patients." (U.S.

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--> House of Representatives, 1970). In this regard, Congress was redressing the interpretation of the Harrison Act that followed upon the closing of the morphine clinics some fifty years earlier. To achieve this clarification, Title I, in Section IV, charged the Secretary of Health, Education, and Welfare, to "determine the appropriate methods of professional practice in the medical treatment of the narcotic addiction of various classes of narcotic addicts." This provision constitutes the initial statutory basis for treatment standards. More important, it clearly stated that the health establishment, not the law enforcement community, would determine the scope of the practice of medicine in this area. The law enforcement sections consolidated all prior federal statutes into the Controlled Substances Act and the Controlled Substances Export and Import Act (Titles II and III, respectively, of the Comprehensive Drug Abuse Prevention and Control Act of 1970). Under this legislation, substances were classified under five schedules "according to their abuse potential, and psychological and physical effects." Methadone was placed in Schedule II, along with such opiate drugs as morphine, codeine, and hydrocodone. Special Action Office for Drug Abuse Presentation One of the most important steps taken by President Nixon was to establish in June 1971 the Special Action Office for Drug Abuse Prevention (SAODAP) in the Executive Office of the President (By Executive Order 11,599, June 17, 1971). In mid-1971, Nixon appointed Dr. Jerome Jaffe as SAODAP director. Within a year, the Drug Abuse Prevention Office and Treatment Act of 1972 (Public Law 92-255, March 21, 1972) gave statutory authority to SAODAP, but limiting setting, on June 30, 1975, as the limit on its existence. The purpose of the 1972 act was to bring the resources of the federal government to bear on drug abuse with the immediate objective of significantly reducing its incidence and developing a comprehensive, coordinated long-term federal strategy to combat drug abuse. The SAODAP direction thus became the "czar" for devising and executing strategies for reducing the demand for drugs. Title II, for example, authorized the director to: make grants and contracts; provide overall planning and policy for all federal drug abuse prevention functions; review current regulations, guidelines, criteria, requirements, and procedures of agencies for consistency with newly established policy; review related federal legislation to assure that all administering agencies viewed drug abuse as a health problem; and coordinate all federal departments and agencies in the fight against drug abuse. Title III required the development of a national strategy directed by the President. Title IV amended the Community Mental Health Centers Act to

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--> include drug abuse treatment and rehabilitation among the array of services offered, to deny approval of any state plan that failed to provide for drug abuse and drug dependence treatment and prevention, and to bar denial or admission to or treatment to drug abusers in hospitals receiving federal funds solely because of their drug abuse or drug dependence. Finally, Title V authorized the creation of the National Institute on Drug Abuse, within the NIMH, effective December 31, 1974, to develop and conduct comprehensive health, education, training, research, and planning programs for the prevention and treatment of drug abuse and for the rehabilitation of drug abusers. (NIDA was actually created in 1973, earlier than authorized, when NIMH, which had been moved out of the NIH in 1967, was reorganized as the Alcohol, Drug Abuse, and Mental Health Administration. The constituent agencies of the new ADAMHA became NIMH, NIDA, and the National Institute of Alcohol Abuse and Alcoholism.) Although the Special Action Office did not exist when FDA issued regulations for methadone Investigational New Drugs (INDs) in 1971, it was significantly involved in the development of 1972 methadone regulations. Dr. Jaffe and his staff actively participated in the drafting of these regulations, in concert with FDA and BNDD staff, as well as in the writing of the 1974 Narcotic Addict Treatment Act. Since SAODAP also controlled federal funding of treatment programs, its role was very important in encouraging and nurturing the establishment and development of methadone treatment programs. Defining the Regulatory Regime: 1970–1974 The methadone regulatory regime—the third set of rules governing methadone treatment was defined in the period 1970 through 1974 by the Comprehensive Drug Abuse Prevention and Control Act of 1970, the FDA methadone regulations for Investigational New Drugs of 1971, the FDA methadone regulations of 1972, and the Narcotic Addict Treatment Act of 1974. We first deal briefly with the clinical antecedents to the FDA regulations, then consider their evolution. Research, Treatment, and Regulation Methadone was approved by FDA for use as an analgesic and antitussive (for prevention and suppression of coughing) on August 13, 1947, when a New

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--> Drug Application (NDA 6134) was granted for Dolophine to Eli Lilly & Co.3 Methadone was first studied in this country in 1946 at the U.S. Public Health Service Hospital in Lexington, Kentucky.4 It was found to be similar to morphine in its effects but possibly longer acting. Clinical research showed that opiate withdrawal syndrome could be treated effectively by substituting methadone for morphine and slowly reducing the dose over a 7–10 day period. Its primary use in addiction treatment was to withdraw addicts from heroin, well before methadone maintenance treatment was developed. In 1962, Vincent Dole and Marie Nyswander at Rockefeller University began planning clinical studies to use methadone with carefully selected narcotic addicts in New York City. Their research, which started in late 1963, and was first reported in Dole (1965), demonstrated that methadone could be used to treat intractable heroin addicts by maintenance, not detoxification. Beginning in the mid-1960s, the findings of Dole, Nyswander, and Mary Jeanne Kreek were reported in a number of papers (Dole, et al., 1966). As a result, many interested researchers and clinicians visited Rockefeller to learn about their treatment protocols. Annual conferences, held from 1968 through 1971, and sponsored by the National Association for the Prevention of Addiction to Narcotics, resulted in the rapid dissemination of this research and the creation of a close professional network to promote the use of methadone in treating heroin addiction (Besteman interview). The course of the transition from clinical research to greater use of methadone for treatment was unusual, however. In 1947, when FDA approved Lilly's NDA for methadone, it required only the demonstration of safety under the 1938 Federal Food, Drug, and Cosmetic Act (FFDCA). The 1962 amendments to the FFDCA added the requirement that FDA also evaluate the effectiveness of new drugs before their introduction to the market. Although the use of methadone for treating narcotic addiction was a new "indication for use" that fell under the effectiveness requirement of the 1962 amendments, FDA did not become deeply involved in its evaluation until the late 1960s and early 1970s. The normal route for seeking approval of a new drug or a "new indication" is for the sponsor of the drug (usually its manufacturer) to obtain an Investigational New Drug (IND) authorization. Under an IND, evidence of safety and effectiveness based on well-controlled clinical studies is developed in support of an NDA (or a Supplemental NDA in the case of a new indication 3   "Dolophine" was derived from "dolor" for pain. The street name for dolophine, which is a wafer form of methadone, is "dolly." A persistent but false belief is that the name derives from Adolf Hitler. 4   It is worth noting that the Public Health Service was engaged in addiction research well before the adoption in 1966 of the Narcotic Addict Rehabilitation Act.

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--> for a previously approved drug). This course was not initially pursued in the case of methadone, perhaps because FDA was in the early stages of implementing the 1962 act and also because there was no pharmaceutical sponsor. Dole's planning in the mid-1960s included an assessment of the legal authority of Rockefeller University to conduct such research. Although Dole and Nyswander's studies provided the clinical demonstration of effectiveness, they were not done under an IND, as FDA rules did not require one.5 Dole viewed the Treasury's Bureau of Narcotics (FBN) as the primary federal agency that might have regulatory authority over his proposed research, and the key question was whether research using methadone to maintain heroin addicts as part of a treatment program in New York City was within the domain of the professional practice of medicine or was another form of trafficking, as FBN had claimed with respect to the morphine clinics some 40 years earlier (Dole, 1989). After extensive consultation with university lawyers and officials, Dole concluded that prior Supreme Court decisions did not bar the use of methadone in ''in the course of professional treatment." The FBN view, however, was that maintenance of narcotic addiction with any narcotic drug fell outside the normal course of professional treatment. Dole recalls a visit by an FBN agent who informed him that he was breaking the law and that he would be put in jail. Dole challenged his visitor to have the agency sue him, a distinguished member of the faculty of Rockefeller University. Nonplussed, the agent left, only to return a short time later with the message that the research could be conducted, but only under direction of the Bureau. Dole, secure in his knowledge of the limits of FBN authority, rejected this concession as well (telephone interview with Dr. Vincent Dole, December 1993). For roughly a five-year period, from 1965 through 1970, Dole's research went forward, harassed by the FBN, as Dole recalls, but without regulatory encumbrances. 5   Before August 1962, no one had to file an IND with FDA; one simply had to comply with certain labeling and record-keeping requirements. The 1962 amendments expanded the IND provisions of the FFDCA and, even before the act was signed, FDA issued new regulations that required IND filings with FDA. Even under the new regulations, FDA did not attempt to require an IND for an individual physician who used a drug for research (or for a medical use other than FDA-approved), if the drug was in compliance with the law before the physician got it. Thus, methadone manufactured by Lilly and shipped to Rockefeller University's pharmacy and labeled in accord with the Lilly NDA was "lawful."

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--> Methadone IND Regulations During the mid to late 1960s, the period when Dole's results were beginning to attract the interest of researchers and clinicians, the FDA for its part showed little interest in the use of methadone. It simultaneously resisted the submission of an NDA for methadone on the grounds that there were no supporting scientific data developed under INDs, and did little to encourage IND submissions, with some FDA officials expressing skepticism that Dole was realizing the results being claimed (Besteman interview). In a direct challenge to this situation, however, Dr. Sidney Cohen, director of the NIMH's Division of Narcotic Addiction and Drug Abuse (DNADA) in 1968–1969, applied for an IND for methadone clinical research (Besteman interview). A distinguished clinician and researcher who had come to government service from University of California, Los Angeles, Cohen was granted an IND. Out of concern that investigators participating under the Cohen IND be reputable and responsible, Cohen, and Dr. Richard Phillipson, his co-investigator, restricted them to NIMH grantees. The participants, who may have numbered as many as 15 to 20, reflected diverse philosophies of treatment; for example, Dr. William Wieland in Philadelphia advocated high doses of methadone, while Dr. Ray Knowles in St. Louis was more conservative. NIMH grantees were funded mainly by direct grants from DNADA, with most of the grants going directly to community mental health centers. Later, in the mid-1970s, funds were channeled through NIDA-funded state drug treatment programs. Given Dole's results, and following the Cohen IND, other physicians sought and received INDs, with relatively little difficulty; FDA has indicated that more than 300 INDs were issued. In the eyes of the FDA, the situation was getting out of control. Consequently, in 1970, as controlled substances legislation was moving through Congress, the FDA sought to strengthen its control over the methadone treatment being conducted under INDs. Although the IND-based research generated data on the use of methadone for treatment, these data were insufficient to justify the drug's approval as safe and effective and FDA concluded that further research was needed. It issued a proposed rule dealing with IND protocols for methadone treatment on June 11, 1970 (35 FR 9014). On April 2, 1971, a final rule of 2 1/2 pages specified the conditions of investigational use; the rule also responded to a BNDD regulation on IND requirements for controlled substances (see below), to the off-label use concerns of the FDA, and to the easy availability of methadone through community pharmacies and "script"-writing physicians. The IND had in fact become a means for providing narcotic addiction treatment under the ostensible purpose of research. Although these IND-based treatment efforts, thinly disguised as research, resulted in annual reports that

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--> met FDA's IND reporting requirements for patient safety data, the protocols were not designed to obtain effectiveness data in support of an NDA and little attention was paid to the reports. (These treatment efforts did generate a large body of data on a large number of heroin addicts. The DNADA monitored the Cohen-IND investigators' reports for adverse effects of the drug, as did FDA for all INDs, but no effort was made by either agency to review and analyze the data systematically. The primary value of these data, when the 1972 FDA regulations were proposed and issued, was that they revealed no major negative consequences from treatment of addicts with methadone). Even though the 1971 IND regulations were designed to permit the use of methadone for treatment of heroin addiction—under very strict federal controls—they were so restrictive that they discouraged its use. For example, the "acceptable protocol" that was to guide programs promoted rehabilitation and stipulated such measures of efficacy as arrest record, extent of alcohol abuse, extent of drug abuse, occupational adjustment, social adjustment, and "withdrawal from methadone and achievement of an enduring drug free status." In addition, the protocol also recommended that "initial dosage was to be low; for example, 20 milligrams per day," urinalyses were to be conducted weekly, and ''participants who have maintained satisfactory adjustment over an extended period'' were to be considered for discontinuation. Nevertheless, these 1971 regulations set the stage for 1972 FDA regulations that supplanted them. 1972 Regulations New methadone regulations were proposed by FDA in April 1972 and issued in final form on December 15, 1972, (37 FR 26790). Although modified several times in the two decades since then, they established the basic DHHS framework that still exists for the regulation of methadone and constitutes the third layer of regulation, additional to the traditional approaches to regulation taken historically by the FDA and DEA (and its predecessors). The regulations removed methadone from general distribution and established controls over its use, literally on a patient by patient basis, through physician registration and treatment programs with characteristics prescribed in the regulations. Two types of treatment—detoxification and maintenance—were defined. The former involved using methadone "as a substitute narcotic drug in decreasing doses to reach a drug free state in a period not to exceed 21 days" in order to "withdraw an individual who is dependent on heroin or other morphine-like drugs from the use of these drugs." Methadone maintenance, the provision of which was to be restricted to methadone treatment programs, involved using methadone "at relatively stable doses" for more than 21 days along with the appropriate social and medical services. The rule made it clear

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--> that although the goal of treatment was an "eventual drug free state," it differed from the 1971 regulation in the recognition "that for some patients the drug may be needed for long periods of time" (37 FR 26795, December 15, 1972). In order to deny physicians, pharmacies, hospitals, or treatment programs the authority to prescribe, administer, or dispense methadone without prior approval by the FDA and the appropriate state agency, the regulations specified certain "organizational structures" as conditions of approval of participating programs. A two-tiered system was stipulated. The first tier—"methadone treatment programs"—provided comprehensive services using methadone for either detoxification or maintenance treatment of narcotic addicts, including initial patient evaluation. All facilities, hospitals, and outpatient units that conducted initial evaluations and dispensed the medication were considered separate programs, even though outpatient units might be part of a primary ''centralized organizational structure." The second tier, a ''methadone treatment medication units—referred to a facility within a treatment program that was "geographically dispersed" from the primary facility and other medical units and restricted to dispensing methadone and collecting urines to test for narcotic drugs. Minimum program services, in addition to the dispensing of methadone, were to include counseling, rehabilitation, and other social services to help the patient "become a well functioning member of society." Programs not physically within a hospital were required to have formal agreements with some responsible hospital official to ensure that both inpatient and outpatient hospital care was fully available to any patient needing it. Neither the program sponsor nor the hospital was obligated to be financially responsible for such care. The regulation also required that individual physicians who wished to provide methadone treatment apply and be approved as a "program." In order to operate a methadone treatment program, the regulation required simultaneous submission of an application to FDA and to the state authority for approval. In addition, before FDA approved a program it was to "first consult" with BNDD to determine compliance with the controlled substance law. Each specific physical site at which medication was to be dispensed required approval—for initial use or termination of use of methadone, or relocation of the site of use. Similarly, revocation of a program by a state authority required FDA revocation; FDA revocation required consultation with DEA. Medication units were limited to 30 patients, referred by the primary unit, who did not need the "frequent counseling, rehabilitative, and other services" of the primary facility and who had demonstrated "progress toward rehabilitation." Approval of medication units was by the FDA and the state authority, based on the number of such units in a geographic area. The medication unit

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--> proposed rule (52 FR 37047, October 2, 1987) and culminated in a final rule (54 FR 8954, March 2, 1989) at the end of the decade. In the 1987 proposed rule, the FDA and NIDA, in an effort to put the best face on the unenthusiastic 1983 response by the provider community to converting the regulations to guidelines, indicated that they had retained the "current requirements necessary to achieve the goals" of the 1974 NATA, but were proposing to "streamline" the regulation and to "promote more efficient operation of methadone programs." The most significant revision proposed was to develop separate guidelines "consisting of those provisions of the current regulation that are not legal requirements." Therefore, language beginning with "It is recommended practice that" was to be dropped from the regulation and incorporated into an accompanying guidance document. The 1987 proposed rule, issued by the FDA and NIDA, advanced the following changes in the methadone regulation: that detoxification treatment be divided into short-term (<21 days) and long-term (>21 and <180 days) treatment; that the minimum staffing ratio of one counselor to 50 patients be eliminated; that blood tests be allowed as ways to conduct initial drug screening or to meet the monthly testing requirements for six-day take-home patients; that the 72-hour notification of FDA and the pertinent state authority for methadone doses greater than 100 mg be eliminated; that special adverse reaction reporting requirements for methadone be eliminated and reliance placed upon general FDA reporting requirements; that a supervising counselor be allowed to conduct the annual review of the patient's treatment plan for "certain qualified patients" who had been in treatment for 3 years or longer; and that the requirement of an annual report of methadone treatment programs to the FDA be dropped. The agencies rejected the option that the federal government rely exclusively on state and local regulations. Federal involvement was required by NATA to "ensure that only bona fide narcotic addicts" were admitted to treatment, "to limit the potential for illicit diversion," and to set forth "minimum standards for the treatment of narcotic addicts with methadone." However, throughout the proposal, FDA and NIDA proposed to defer to the judgment of treatment programs and to leave to state and local governments the responsibility for stricter regulation. The summary noted that authority existed for the federal government to contract with states for inspection and compliance with the federal regulations. The suggestion that the federal government rely on the (then) Joint Commission on the Accreditation of Hospitals and its alcohol guideline was rejected as inappropriate to drug abuse.

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--> 1989 Final Rule The FDA and NIDA issued a final rule on March 2, 1989, based on comments on the 1987 proposed (54 FR 8954). Although the rule modified the methadone regulations somewhat, it left the fundamental structure intact. The major changes to the regulations as issued in 1980 included the following: detoxification was separated into short- and long-term, the former being a maximum of 30 days and the latter a maximum of 180 days; a specified counselor-patient ratio was deleted; treatment programs were allowed to use other procedures besides urinalysis, such as blood testing, to test for drugs of abuse; the 72-hour notification of FDA and state authority for doses above 100 mg was eliminated, but written justification in the patient record was still required; the review of a patient's annual treatment plan by a physician was not required for model patients in treatment for 3 years; the serology test for syphilis could be omitted if a patient's veins were so severely damaged as to preclude obtaining blood; expanded counseling for pregnant women was required; an inadvertently omitted requirement that a physician date and sign the patient record within 72 hours of first administration of methadone was reinstated; and the special adverse reaction reporting requirement for methadone and the annual report to FDA were eliminated. Some provider comments on the 1987 proposed rule reflected a fear that removal of rehabilitation services requirements would weaken the emphasis on rehabilitation. The agencies' response was that they believed "that a program's staff is in the best position to determine what services are needed" (54 FR 8956, March 2, 1989). A suggestion that the roles of physicians, counseling directors, and counselors be clearly delineated evoked the response that the regulation's purpose, as defined by NATA, was "to develop "appropriate methods of professional practice in the medical treatment" of narcotic addiction. Similarly, the response to a request for criteria differentiating between shortand long-term detoxification left that judgment with the treatment program. On the other hand, the FDA and NIDA rejected a suggestion that the requirement for 6-days per week observation of a patient receiving greater than 100 mg of methadone represented interference in the professional judgment of a physician for which there was "no medical justification." Rather, the agencies held that such doses "present a high risk of diversion" and that "concerns about the possibility of diversion must outweigh concerns about infringing on the clinical judgment of the program's physician" (54 FR 8959).

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--> 1989 Guidance Document Concurrently, FDA and NIDA issued a six-page guidance document, which noted that the regulations, over time, had recommended "certain practices" that were not actually required. The document was consolidating these recommended practices (the "shoulds") for medical and other services for the treatment of narcotic addicts; the requirements (the "shalls") were retained in the regulations. The guidance document dealt with services; hospital affiliation; medication units; current physiological dependence; drug screening urinalysis; contents of medical evaluation; admission evaluation; initial treatment plans and their periodic evaluation; pregnant patients, staffing; and initial, maintenance, take-home, and initial detoxification dosage; methadone formulation; and discontinuation of methadone use (both involuntary and voluntary). The document stated that "medical services and counseling, rehabilitative, and other social services" should normally be available at the primary outpatient facility but might be provided under contract with other organizations, either on-site or elsewhere. If not physically within a hospital, a formal agreement should exist indicating that hospital care, including emergency, inpatient, and ambulatory care, is "fully available" to any patient needing it. Medication units should serve a geographic area separate and distinct from the primary facility and of "reasonable size" relative to the treatment space. In determining ''current physiological dependence," the report advised physicians to consider both signs and symptoms of intoxication and early signs of withdrawal. In the use of urinalysis for program decisions, the guidance document advised programs to "show evidence of reasonable confirmatory laboratory analysis." Urinalysis was described as "one clinical tool" for diagnosis and making treatment plans and "one technique" for program evaluation by monitoring pre- and post-treatment drug use patterns. The document stated that "a person could be currently dependent on narcotic drugs without having a positive urine test for narcotics [i.e., could produce a false negative]," or a person "could have a positive urine test for narcotics and not be currently physiologically dependent [i.e., could produce a false positive],'' and thus testing should not be used as the exclusive basis for admission for treatment. The contents of the medical evaluation were specified in detail. The acquisition of information about a patient's psychosocial, economic, and family background that revealed "strengths and weaknesses" was left to individual programs. Dosage was spelled out for initiation of treatment (15–30 mg for heavy users of heroin, with lesser amounts 4 to 8 hours later; one-half these amounts

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--> for those with "little or no tolerance"), and the range of maintenance was indicated as between 40 mg and 100 mg daily. 1989 Interim Methadone Maintenance Proposal On March 2, 1989, simultaneously with publication of the revision of the regulations and the issuance of the guidance document, two other actions were taken by FDA and NIDA: a proposed rule was issued on interim methadone maintenance; and comment was solicited on a pilot study on "improved measures of methadone performance." Interim methadone maintenance was a variation from established methadone practice, by which methadone, but no other services, could be provided on a temporary basis to addicted persons for whom treatment slots were available; it was being proposed by the FDA and NIDA "in response to the HIV epidemic in the intravenous (IV) drug abusing population" and was "intended to help reduce the spread of HIV infection" (54 FR 8973, March 2, 1989). HIV was ''making massive inroads" among intervenous drug users; methadone treatment, by reducing the consumption of heroin by needle sharing, could therefore reduce the spread of HIV.6 Under the proposal, methadone maintenance treatment was to be categorized as "comprehensive" and "interim." The former was methadone maintenance treatment as defined in the existing regulations. Although "interim" treatment was to be provided only by comprehensive treatment programs (i.e., programs offering only interim treatment were prohibited), it was intended to give programs the flexibility to "dispense methadone to medically evaluated narcotic addicts who are awaiting placement in comprehensive maintenance treatment." Programs would be required to provide a medical examination and service, but not rehabilitative services. They would also be required to "counsel patients on reducing the risk of HIV-transmission." Methadone would have to be ingested under observation; therefore, random drug screening tests would be not be required. Take-home medication would be prohibited, so clinics would have to be open seven days a week. The initial treatment plan and periodic plan evaluation required of "comprehensive" programs would not be 6   The proposal arose from increased concern within the Public Health Service about the general HIV epidemic and the increasing spread of HIV to intravenous drug users. In addition, a study at Beth Israel Medical Center, New York, funded by the Centers for Disease Control, showed methadone to be effective in reducing needle use among methadone patients.

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--> required for "interim" treatment. Nor would the assignment of a primary counselor to a patient be required. Under the proposal, programs would be required "to establish and follow reasonable written priorities, which may take into account medical and rehabilitative factors, for transferring patients from interim maintenance treatment to comprehensive maintenance treatment." Transfer was anticipated by FDA and NIDA after "a relatively brief period," but no times were specified for such transfer. However, if a patient was continued in interim treatment for six months, a formal evaluation would be required to see "how the patient meets the transfer priority criteria." In general, response to the "interim" maintenance proposal rule was strongly negative, especially by providers and state methadone authorities, although the American Medical Association was supportive. In April the FDA and NIDA extended the initial comment period until May 3, 1989. On December 4, they announced a public hearing for February 28, 1990, and extended the comment period an additional 15 days beyond the hearing (54 FR 50226). Twenty-eight individuals, representing 20 organizations, testified at the hearing. Most of the comment was negative. The evidence on waiting lists showed some regional shortages but did not support a national capacity shortage. Moreover, it was argued that an exemption process at FDA permitted a treatment program to apply for and receive approval to conduct the equivalent of an interim maintenance treatment program, making the proposal unnecessary. The polydrug use of injecting narcotic addicts argued for the counseling and rehabilitative services of a comprehensive program. Importantly, it was pointed out that the resources available to such programs would be reduced if treatment programs also devoted funds to interim maintenance. Providers also feared that providing interim treatment at reduced costs per patient would lead policymakers to reduce their per slot budget allocations for maintenance patients. In light of these factors, many concluded that the proposal would fail in its objective. On May 23, 1990, therefore, the director of NIDA informed his superiors "that today the PHS Methadone Work Group agreed to begin the formal process to rescind the proposal of March 2, 1989." Only the requirement of counseling "on avoidance and transmission" of HIV was to be issued, which would apply to both maintenance and detoxification treatment. Independently of the proposed "interim" methadone regulation, however, efforts were underway within the Public Health Service, in Congress, and elsewhere, to reorganize the Alcohol, Drug Abuse, and Mental Health Administration (ADAMHA). These efforts culminated in the ADAMHA Reorganization Act of 1992 (Public Law 102-321, July 10, 1992), the main purpose of which was to transfer the research portions of the three ADAMHA

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--> institutes—NIDA, the National Institute of Alcoholism and Alcohol Abuse, and the National Institute of Mental Health—to the National Institutes of Health and to create the Substance Abuse and Mental Health Services Administration (SAMHSA) as the home for the service functions of these entitles. However, a secondary provision of the 1992 Act, introduced as an amendment to the House bill by Rep. Henry Waxman, gave a statutory basis to interim maintenance, thus blocking the effort that HHS had begun to rescind its proposed rule of 1989. Consequently, on January 6, 1993, regulations were issued implementing this provision (58 FR 495).7 As of 1994, no treatment program had chosen to implement the optional provisions of the interim methadone maintenance rule other than the requirement of HIV counseling. Assessment of Program Performance Also on March 2, 1989, an advance notice was published (54 FR 8976), which solicited comments on a pilot study "designed to help identify improved measures of methadone program performance and thus enhance the quality of treatment." Subsequently, a Request for Proposals was issued and a contract for the Methadone Treatment Quality Assurance Feasibility Study (MTQAS) was awarded to the Research Triangle Institute of North Carolina. The purpose of this study is to determine the feasibility of developing a performance-based reporting and feedback system and to evaluate how performance-based monitoring might be used to modify the current regulatory structure for methadone. Levo-Alpha-Acetyl-Methadol On July 20, 1993, the FDA and NIDA issued an interim rule (58 FR 38704), effective immediately, with 60 days for public comment, which revised the methadone regulation to provide standards for the use of levo-alpha-acetyl-methadol (LAAM) in the maintenance treatment of narcotic addicts. Simultaneously, the FDA was approving an NDA for LAAM.8 7   This rule was issued jointly by the FDA and SAMHSA. 8   LAAM had been developed originally in 1948 as a synthetic congener of methadone, had been tested in Germany as a narcotic analgesic, and had been examined in this country as a potential narcotic addiction treatment medication in the 1970s. Consideration had languished in the 1980s until the Anti-Drug Abuse Act of 1988 (Public Law 100–690) authorized an expanded drug development effort within NIDA. The newly formed NIDA Medications Development Program then took the leadership

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--> The interim rule noted that the 1989 revision of the methadone regulation had anticipated the approval of other drugs besides methadone for narcotic addiction treatment by changing many methadone-specific terms to general narcotic treatment drug terms. The interim rule reorganized the methadone regulation into three sections: general requirements that applied to all narcotic treatment programs regardless of the drug used; specific requirements applicable to LAAM; and specific requirements for methadone. In one sense, the LAAM interim rule, with its three-part division (general, LAAM, and methadone) represents the evolution of the methadone regulation into a framework that is able to accept additional medications by the simple addition of new sections and appropriate paragraphs. In another sense, however, it represents the dominance of the beliefs that formed the underpinning of the methadone regulations over fresh thinking about the appropriateness for other antinarcotic medications that are themselves narcotics. The interim rule did revise 21 CFR 291.501, basically unchanged since 1972, which had served as the defacts "preamble" to the methadone regulation.9 The "need for further research" language, which had provided the justification for the hybrid IND-NDA system, was finally replaced by an explicit recognition by the FDA, NIDA, and DEA "that the use of narcotic drugs in the prolonged maintenance of narcotic dependence has been shown to be an effective part of a total treatment effort in the management and rehabilitation of selected narcotic addicts."10 The new section 291.501 noted the dangers of abuse if services and controls were inadequately applied. However, it simply indicated that interested professionals, municipalities, and organizations "should be allowed to use narcotic drugs in the medical treatment of narcotic addiction within a framework of adequate controls designed to protect the individual patients and the community." The interim rule included the following LAAM-related provisions: take-home medications were prohibited; programs were prohibited from admitting individuals into treatment who were under 18 years of age; women of child     in securing its approval as an NDA. 9   This section of the 1972 regulations had been slightly changed in 1977. 10   Although the need for "more research" was a legal justification for the hybrid 1972 IND-NDA regulation, it was used politically to resist public approval of methadone treatment as late as the 1988 White House Conference for a Drug Free America. Although the report of that conference recommended that treatment capacity be increased for "a full range of treatment approaches," including self-help groups, short-term treatment (both inpatient and outpatient), and long-term residential care, it also proposed that an independent organization evaluate the efficacy of methadone treatment.

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--> bearing age seeking treatment were required to have a monthly pregnancy test; patients could not receive the medication more often than every other day at doses, frequencies, and under conditions of use prescribed in the approved labeling; for a previously stabilized methadone patient, initial doses were to be 1.3 times the daily methadone dose, not to exceed 120 mg of LAAM; a licensed physician was required to assume responsibility for the amount of drug dispensed and for recording changes in dosage in the patient's record; the drug was to be dispensed in liquid form, with a taste and color distinguishable from methadone. The NDA for LAAM was approved by FDA on July 9, 1993 and LAAM was then rescheduled from a schedule I controlled substance to a schedule II substance (58 FR 43795, August 18, 1993). Comments on the interim rule challenged the assertion that treatment capacity would be increased by the longer duration of LAAM, criticized the prohibition on take-homes, sought clarification on dosage in relation to methadone doses, questioned the need for monthly pregnancy testing on grounds of costs, asked whether methadone treatment programs would be automatically approved to use LAAM, and complained that the FDA-approved label had not been published with the rule. California proprietary providers objected to the requirement that a physician complete and record initial patient evaluation findings before administering the medication, preferring that the physician either sign in advance or review the decision of a "health professional" within 72 hours of initial dose. Whatever the limits imposed on LAAM by the federal methadone regulations, the implementation of LAAM regulation revealed that state regulations of the use of narcotics for the treatment of narcotic addiction were generally more constraining. In a memorandum of November 4, 1993, addressed to Dr. Frank Vocci, of the NIDA Medications Development Program, H. Alex Bradford, Chief Executive Officer of the BioDevelopment Corporation, the commercial sponsor of LAAM, outlined the complexity of the state approval process. He identified "five general areas" that needed to be addressed before an individual clinic (i.e., treatment program) could purchase LAAM: Existing state treatment regulations, which covered methadone, needed to be modified for LAAM, which in many states required legislation unless an interim administrative process was employed. The rescheduling of LAAM (as a controlled substance) was required in many states. The addition of LAAM to the state formulary of medications approved for treating opiate dependence was required. LAAM needed to be included in the list of reimbursable medications for treating opioid dependence.

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--> The approval of LAAM's use in the clinic by county and local organizations having responsibility for overseeing the treatment clinics in their jurisdiction was often required. The Bradford memorandum opens a window onto state regulation of the use of narcotics for narcotic addiction that shows that it is very extensive and considerably more variable than federal regulation. Viewed historically, state regulation is far more developed today than it was when methadone was initially approved by FDA. Summary Although there has been some evolution and refinement, the methadone (and now LAAM) regulations in 1994 are fundamentally based on several assumptions that led to their issuance in 1972: That use of a narcotic drug to treat narcotic addiction is an unusual practice posing special risks to patients, both those truly addicted and those who might be more appropriately treated without narcotic drugs; That the desirability and availability of methadone created an unusual potential for drug diversion to illicit uses, posing special risks to society (see chapter 4); That the regulatory controls imposed by the Federal Food, Drug, and Cosmetic Act and the Controlled Substances Act, as well as by state and local laws, on all other therapeutic drugs that also have a potential for abuse are inadequate to protect patients and society from these special risks; and That a third set of federal regulations, thrusting FDA into a direct role of overseeing medical practice on a patient-by-patient basis, is necessary to assure protection. In the course of its deliberations, the committee concluded that these assumptions are flawed and must be reexamined by HHS. Prior reviews of the regulations, proposed rules, final rules, guidelines, and public discussion have questioned these assumptions to some extent, but the comprehensive and public reevaluation of them has yet to take place. Although the committee does support some continued special regulation of methadone, it finds many of the current requirements excessively intrusive into medical practice, inimical to proper patient care and public health, and unnecessary to protect public safety, as specified in chapters 7 and 8.

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--> References Besteman, K. (1992). Federal Leadership in Building the National Drug Treatment System, Institute of Medicine. Treating Drug Problems , Vol. 2, Gertein, DR and Harwood, HJ, eds. National Academy Press, Washington, D.C. Center for Drug Evaluation and Research of the Food and Drug Administration and the National Institute on Drug Abuse. 1989. Guidance on the Use of Methadone in Maintenance and Detoxification Treatment of Narcotic Addicts. March. Conversation with Vincent Dole. 1994. Addiction (89):23–29. Dole, VP, and Nyswander, M. 1965. A medical treatment for diacetylmorphine (heroin) addiction. Journal of the American Medical Association 193:80–84 Dole, VP, Nyswander, ME, and Kreek, MJ. 1966. Narcotic blockade: A medical technique for stopping heroin use by addicts. Transactions of the Association of American Physicians 79:122–136. Dole, VP. (1989). In Courtwright, D, Joseph, H, Des Jarlais, D, Addicts Who Survived: An Oral History of Narcotic Use in America, 1923–1965 , Knoxville, University of Tennessee Press 331–343. Draft Final Rule, Food and Drug Administration, National Institute of Drug Abuse, "Methadone in maintenance and detoxification treatment of narcotic addicts; human immunodeficiency virus counseling," unpublished, n.d. Institute of Medicine. 1991. Research and Service Programs in the PHS: Challenges in Organization. Washington, D.C., National Academy Press. Letters to the FDA Dockets Management Branch from the following: Nina Peyser, Executive Director, Chemical Dependency Institute, Beth Israel Medical Center, New York, NY, August 24, 1994; Forest Tennant, MD, Dr.P.H., Community Health Projects Medical Group, West Covina, Calif., September 7, 1993; James L. Sorensen, Ph.D., Chief, Substance Abuse Services, San Francisco General Hospital, San Francisco, Calif., September 14, 1993; Frank McGurk, Chairperson, New York Committee of Methadone Program Administrators, New York, NY, September 15, 1993; Melvin Sabshin, M.D., Medical Director, American Psychiatric Association, Washington, D.C., September 22, 1993; and Andrew M. Mecca, Dr.P.H., Director, Department of Alcohol and Drug Programs, State of California-Health and Welfare Agency, Sacramento, Calif., September 27, 1993. Letters to FDA Dockets Management Branch from the following: Kenneth Teruya Akinaka, M.R.A., Quality Improvement Coordinator, Bay Area Addiction Research and Treatment, San Francisco, Calif., 9/14/93; and Robert B. Kahn, Ph.D., President, California Organization of Methadone Providers, San Diego, Calif., September 23, 1993. Memorandum to Dr. John Gregrich, ONDCP, Mr. Chris Petula, Senate Judiciary Committee, Ms. Denise Courier, Drug Enforcement Administration, and Dr. Frank Vocci, Medications Development Division, NIDA, from H. Alex Bradford, CEO, BioDevelopment Corporation, November 4, 1993. Memorandum to Chairman, Methadone Retrospective Review Team, from Peter H. Reinstein, M.D., Acting Director, Office of Drugs, Food and Drug Administration, re "Revised Final Report—Retrospective Review of Methadone Regulations," September 9, 1983.

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--> Memorandum to Chairman, Retrospective Review Committee, from Edwin V. Dutra, Jr., Chairman, re "Methadone Retrospective Review of the Methadone Regulations," August 26, 1983. Memorandum from Charles R. Schuster, Director, NIDA, to Dr. Frederick Goodwin, Administrator, Alcohol, Drug Abuse, and Mental Health Administration, Mr. Mark Barnes, Counsel to the Secretary, Dr. James Mason, Assistant Secretary for Health, and Dr. Herbert Kleber, Office of National Drug Control Policy, "Federal Methadone Regulation—Proposed Revision to Allow Interim Treatment," May 23, 1990. Nightingale, SL. 1993. Associate Commissioner for Health Affairs, Food and Drug Administration, letter to Richard A. Rettig, Ph.D. (June 21). Revisions to the Federal Methadone Regulation (21 CFR 291.505), document provided by National Institute of Drug Abuse, n.d. U.S. Senate, Committee on Judiciary. 1973a. Narcotic Addict Treatment Act Hearings, 93rd Congress, 1st Session (April 5). p. 697 U.S. Senate, Committee on the Judiciary. 1973b. Methadone Diversion Control Act Report No. 93–192, 93rd Congress, 1st Session (June 4). U.S. House of Representatives, Interstate and Foreign Commerce Committee. 1970. Comprehensive Drug Abuse Prevention and Control Act of 1970 Report No. 91–1444, 91st Congress, 2nd Session (September 10). U.S. House of Representatives, Interstate and Foreign Commerce Committee. 1974. Narcotic Addict Treatment Act Report No. 93–884, 93rd Congress, 2nd Session (March 7). Yancowitz SR, Des Jarlais DC, Peyser NP, Drew E, Friedmann P, Trigg HL, and Robinson JW. A randomized trial of an interim methadone maintenance clinic. Am J Public Health 81:1185–1191, September 1991.