Ann. N.Y. Acad. Sci. ISSN 0077-8923
`
`ANNALS OF THE NEW YORK ACADEMY OF SCIENCES
`Issue: Addiction Reviews
`
`The history of the development of buprenorphine
`as an addiction therapeutic
`
`Nancy D. Campbell1 and Anne M. Lovell2
`1Department of Science and Technology Studies, Rensselaer Polytechnic Institute, Troy, New York. 2Institut National de la
`Sant´e et de la Recherche M´edicale, Universit´e Paris Ren´e Descartes, Paris, France.
`
`Address for correspondence: Nancy D. Campbell, Ph.D., Department of Science and Technology Studies, Sage Labs 5508,
`Rensselaer Polytechnic Institute, 110 Eighth Street, Troy, NY 12180. campbell@rpi.edu
`
`This paper traces the early 21st century success of the agonist–antagonist buprenorphine and the combination drug
`buprenorphine with naloxone within the broader quest to develop addiction therapeutics that began in the 1920s
`as the search for a nonaddictive analgesic. Drawing on archival research, document analysis, and interviews with
`contemporary actors, this paper situates the social organization of laboratory-based and clinical research within the
`domestic and international confluence of several issues, including research ethics, drug regulation, public attitudes,
`tensions around definitions of drug addiction, and the evolving roles of the pharmaceutical industry. The fervor
`that drove the champions of buprenorphine must be understood in relation to (1) the material work of research and
`pharmaceutical manufacturing; (2) the symbolic role of buprenorphine as a solution to numerous problems with
`addiction treatment evident by the mid-1970s; the destigmatization and individualization of addicts as patients; and
`(3) the complex configurations of public and private partnerships.
`
`Keywords: addiction therapeutics; buprenorphine; narcotic antagonists; partial agonist–antagonists
`
`The early 20th century project to develop
`nonaddicting analgesics
`
`Addiction therapeutics arose within the historical
`context of efforts to develop a nonaddicting anal-
`gesic that began in the United States in the early
`1920s. Early 20th century efforts to respond to the
`“opium problem,” through regulation and control
`at the source of supply and to address public health
`concerns through innovation in the research lab-
`oratory set the stage for the gradual shift in re-
`searchers’ interests toward developing a treatment
`for addiction therapeutics. Diplomacy directed to-
`ward control of opium and its derivatives drove
`the earliest interactions between the United States
`and the League of Nations. Policy elites considered
`the opium problem to be an acute threat to na-
`tional public health that could only be met through
`international collaboration on drug control policy
`(p. 52 in Ref. 1).1,2 Pharmaceutical industry influ-
`ence was typically represented by national govern-
`ments at the time. Lacking in-house research ca-
`
`pacity, the U.S. industrial and academic pharmacol-
`ogy was so underdeveloped that Harvard University
`pharmacologist Reid Hunt urged the chair of the
`Division of Medical Sciences (DMS) of the National
`Academies of Science (NAS), National Research
`Council (NRC) to strengthen drug discovery, “the
`field of medical research in which the United States is
`most conspicuously backward.”3 This rationale later
`led the NRC to adopt a committee formed to coor-
`dinate efforts to identify “non-habit forming opiates
`and local anesthetics so that the use of opium and
`cocaine (the abuse of which almost balances the ben-
`efits) may be restricted or abolished.”3 Convened in
`1921 by the New York City Bureau of Social Hygiene,
`the Committee on Drug Addiction (CDA) under-
`took the search for morphine substitutes as a way
`to attack the root of the “opium problem,” which it
`considered to be not “vicious” (nonmedical) con-
`sumption but medical use leading to addiction. The
`CDA published The Opium Problem (1928), a hefty
`compendium reviewing 4,000 studies, which found
`that while the “consensus of opinion of the authors
`
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`Campbell & Lovell
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`History and development of buprenorphine
`
`reviewed is that the majority of cases of chronic
`opium intoxication lies in the therapeutic use of the
`drug,” there was rising heroin use for “purposes of
`dissipation” (p. 13).4 Committee sponsorship was
`assumed by the Rockefeller Foundation from 1932
`to 1939, after which the CDA became part of the
`NAS/NRC and was relatively self-sustaining through
`modest contributions from the pharmaceutical in-
`dustry and National Institute of Health (NIH; in
`1949 renamed National Institutes of Health). The
`Committee undertook chemical dissection of the
`morphine molecule, seeking to dissociate analge-
`sia from addiction liability and emphasizing direct
`manipulation of the morphine molecule to develop
`nonaddictive substitutes for each known medical
`use of morphine.
`The solution to the “opium problem” was first
`sought at the laboratory bench at a time when the
`United States was becoming a major player within
`the evolving international drug control framework.
`For such a narrowly tailored goal to be understood
`as meeting a broad social problem of unclear etiol-
`ogy, it had to be translated into a fundable research
`program. Reliable methods to test compounds in
`animals and human beings had to be developed
`and validated. In the CDA’s first decade, some
`150 compounds were produced and evaluated; all
`but one—Metopon (5-methylhydromorphone)—
`demonstrated the elusiveness of the goal.5
`Although iatrogenic addiction had declined with
`changes in medical practice,6 physicians remained
`the chief vectors of opiate addiction in the early
`20th century. The Committee’s goals dovetailed
`with an American Medical Association (AMA) re-
`form agenda to “reduce indications for opiates to
`an irreducible minimum” (p. 95).7 CDA leader-
`ship supported scientific investigation of narcotics,
`including analyses of the chemical and biological
`literature on addiction alkaloids; formulation of
`rules and regulations for legitimate use of alkaloids
`having addiction properties, and education of physi-
`cians and the public about these rules; and “replace-
`ment of all present use of addiction alkaloids by
`substitutes having no addiction properties” (p. 11)
`(emphasis ours).8
`Morphine was the Committee’s target because
`it had numerous specific uses in clinical prac-
`tice, many of which, according to the first com-
`mittee report, could already be satisfied by other
`drugs. William C. White, CDA chair from 1929 to
`
`1947, reported that “since no one drug can func-
`tion for all of these uses, it is necessary to replace
`the legitimate uses of morphine with a number of
`substitutes. . . [If it is. . .] possible to substitute
`for all legitimate uses of morphine other chemical
`compounds without addiction properties, it should
`render morphine an unnecessary commodity in in-
`ternational commerce” (p. 11).9 White noted that
`“setting up a machinery for a specific purpose; that
`is, of an attempt at a solution of a definite problem
`of international importance” was new for the NRC
`Divison of Medical Sciences. The Committee was
`charged with reducing legitimate use by decreasing
`physician’s prescriptions and proprietary remedies
`containing narcotics, replacing each use of habit-
`forming drugs with a substance that was not habit-
`forming but capable of producing the medicinal
`action required, and reducing to a minimum the
`legitimate production of alkaloids and thus less-
`ening the necessity for controls.10 The Committee
`was also asked to conduct public education semi-
`nars on the indispensable uses of morphine, to seek
`to prepare by synthesis and analysis compounds
`without addiction fractions, and to study the ef-
`fects of these compounds in animals and later in
`human therapy. White arranged with Morris Fish-
`bein, editor of the Journal of the American Med-
`ical Association, to publish the Committee’s rules
`and regulations governing morphine prescription,
`which was released as The Indispensable Uses of
`Narcotics.11
`The Committee’s research program was a highly
`organized, centrally orchestrated effort—one of the
`first scientific collaborations that focused the U.S.
`government scientific resources on solving a social
`problem. Cooperation between CDA and the U.S.
`Public Health Service (PHS) was secured by strate-
`gic appointments. Clinical studies commenced in
`1933 at the federal penitentiary in Fort Leaven-
`worth, Kansas. However, in 1929 the U.S. Congress
`passed the Porter Bill, authorizing construction of
`“narcotic farms” to rehabilitate addicts. When the
`first U.S. Narcotic Farm opened in Lexington, Ken-
`tucky, in 1935, a tiny research laboratory was housed
`within the 1,500-bed institution. In May 1938, the
`PHS broadened the NIH role in the Committee by
`establishing a chemotherapy unit consisting of sev-
`eral chemists who had been associated with CDA,
`including Nathan B. Eddy, Erich Mosettig, Everett
`L. May, and Lyndon F. Small. The Committee also
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`History and development of buprenorphine
`
`Campbell & Lovell
`
`had at its disposal a PHS clinical researcher, Clifton
`K. Himmelsbach, who had worked with Eddy
`to pioneer the “morphine substitution technique”
`developed to compare the addiction liability of novel
`compounds to morphine. The Himmelsbach tech-
`nique was based on the principle that, “A substance
`which will support and maintain the ‘addicted state’
`is essentially addictive in and of itself ” (p. 26).12
`Research objectives included “new treatment and
`substitution techniques, intensive study of physico-
`chemical, psychiatric, and psychological changes re-
`sulting from single therapeutic and repeated doses
`of morphine in the non-tolerant individual, dur-
`ing stabilized addiction, and in the post-addiction
`state” (p. 30).12 Himmelsbach investigated the rela-
`tionship of chemical structure to addictiveness,13–15
`creating a point-score system to track the “Mor-
`phine Abstinence Syndrome.”16 Based on close ob-
`servation of 65 subjects passing through cycles
`of tolerance, addiction, and withdrawal or “absti-
`nence,” Himmelsbach generated hourly and daily
`point scores that yielded a method for calculating
`the intensity of abstinence and predicting its course.
`He had previously gained insight into techniques
`for quantitatively comparing degrees of “addictive-
`ness” through study of desomorphine and meto-
`pon, a drug developed by Small and marketed for
`chronic pain until the early 1950s. Metopon was
`considered proof of concept for the idea upon which
`the Committee was configured—the dissociation
`of analgesic activity from the undesirable tendency
`to produce dependence and respiratory depression.
`Simultaneously, German chemists produced pethi-
`dine (also called meperidine and trade-named De-
`merol), which was modified during World War II
`to produce methadone, the synthetic analgesic re-
`covered by the Allies during a U.S. Department of
`Commerce investigation of German wartime indus-
`tries.17 During the war, the Committee’s operations
`were suspended, but methadone came to the Com-
`mittee’s attention just as it resumed operation after
`the war’s end (p. 52).18
`Renamed the Committee on Drug Addiction and
`Narcotics (CDAN), the Committee’s first postwar
`meeting was held at the NRC in 1947. Attending
`were Isaac Starr, the newly appointed chair; Harry J.
`Anslinger, chief of the Federal Bureau of Narcotics
`(FBN); Raymond N. Bieter, Head of Pharmacology
`at University of Minnesota Medical School; Dale
`C. Cameron, later chief of the Drug Dependence
`
`Section of the World Health Organization (WHO);
`Maurice H. Seevers, whose University of Michigan
`laboratory the committee had designated for animal
`testing; Eddy and Small from NIH; and representa-
`tives of the Armed Services, FDA, AMA Therapeutic
`Trials Committee, and the American Drug Man-
`ufacturer’s Association. Amidon (methadone) was
`one of the postwar committee’s first considerations,
`as several pharmaceutical firms were interested in
`manufacturing methadone or derivatives. Nathan
`B. Eddy, who had worked with the committee since
`1930, proposed that CDAN serve as a clearinghouse
`to which manufacturers of analgesic drugs submit
`information useful for committee review of addic-
`tion liability and extent of clinical usefulness.
`By the late 1940s, the U.S. government was ac-
`tively attempting to determine the national and in-
`ternational controls to which new synthetic drugs
`would be subjected. At the first postwar CDAN
`meeting, Anslinger gained the Committee’s ap-
`proval of a draft protocol to bring synthetic drugs
`under international control. Whereas the opium-
`producing countries of the developing world viewed
`the new synthetics as dangerous and difficult to con-
`trol, the United States feared it could not stem the
`flow of opiates from producing countries.1 CDAN
`provided recommendations concerning levels of
`control and indications for a drug’s use at the in-
`ternational level. The UN mandated the WHO Ex-
`pert Committee on Drug Dependence (formerly
`“on Habit-Forming Drugs” and later renamed “on
`Drugs Liable to Produce Addiction”) to recommend
`levels of control to regulatory bodies. Along with the
`WHO section that it advised, the Expert Commit-
`tee rapidly forged a principle of balancing medical
`utility against the social risks of abuse. The inter-
`national treaties, the Single Convention of 1961,
`and Psychotropic Convention of 1971 reflected the
`view that the more medically useful a drug, the less
`strict the controls should be.19 In pharmacology,
`Eddy et al. demonstrated that synthetic drugs with
`“morphine-like effects are as good and as bad, as a
`class, as the drugs of natural origin.”20 Eddy played
`a leadership role in the Expert Committee from its
`founding until his death. CDAN members served on
`it and supplied data to it, shaping its drug definitions
`and criteria for control. The Expert Committee, for
`example, depended “in large measure upon receipt
`of information” from American research, funneled
`through CDAN (p. 11).18
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`Campbell & Lovell
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`History and development of buprenorphine
`
`The Addiction Research Center (ARC), as the lab-
`oratory at Lexington was called after 1948 when
`it joined the newly formed National Institute of
`Mental Health (NIMH), studied methadone in
`human subjects, finding that it produced a milder,
`more prolonged version of the abstinence syndrome
`than other opiates, according to the Himmelsbach
`scale. Research Director Harris Isbell, who had re-
`placed Himmelsbach, instituted methadone detox-
`ification at Lexington after 1948 for clinical man-
`agement of opiate withdrawal. Isbell later opposed
`using methadone for maintenance given the re-
`sults of studies he and Abraham Wikler conducted
`on former morphine and/or heroin addicts in the
`late 1940s indicating that the subjects expressed
`increased satisfaction as dosage increased.21 They
`concluded that “narcotic drug addicts would abuse
`methadone and would become habituated to it if it
`were freely available and not controlled” (p. 892).21
`They also noted that methadone “completely alle-
`viated the morphine abstinence syndrome in man”
`and itself exhibited a mild abstinence syndrome.
`On the basis of their findings of “satisfactory sub-
`jective reaction” to methadone, they argued that
`methadone would present a potentially serious pub-
`lic health problem if manufacture and distribution
`were not controlled.22
`Despite controls, methadone was used as an
`“office-based” addiction treatment by a handful
`of physicians who prescribed it in the 1950s; the
`New York State Department of Mental Health ran
`an informal methadone maintenance program in
`1959.23 However, the rabidly antimaintenance Fed-
`eral Bureau of Narcotics (FBN) harassed physi-
`cians who prescribed methadone or other opiates.
`Neither Anslinger nor CDAN researchers consid-
`ered maintenance a viable solution to the prob-
`lem of “unsafe analgesics,” as it was framed. By the
`1950s, the Committee’s drug development hopes
`fastened upon another class of drugs—the narcotic
`antagonists—as an alternative to agonists like mor-
`phine and methadone. A spirit of experimentality
`permeated the organizations and research networks
`through which addiction researchers and clinicians
`then worked.
`The mid-20th century project to develop
`narcotic antagonists as “safe analgesics”
`
`In 1963, Isbell and Wikler retired, handing over the
`ARC to neuropharmacologist William R. Martin,
`
`who joined the group in 1957. Martin studied the
`underlying neural mechanisms of addiction, and
`had immersed himself in Himmelsbach’s early find-
`ings, becoming convinced that tolerance was an ex-
`tremely complex neuronal phenomenon. He set out
`to understand the “neuronal events that are respon-
`sible for morphine’s action as well as for a develop-
`ment of physical dependence and the emergence of
`the phenomena of early and protracted abstinence”
`(p. 108).24 Martin, a physician and World War II
`Army veteran, had prepared a doctorate in neu-
`ropharmacology under Klaus R. Unna, who, while
`working for Merck, discovered that nalorphine, a
`narcotic antagonist, could “prevent or abolish the
`action of morphine.”25 Martin worked in a highly
`original and theoretical way with a close-knit circle
`of chemists innovating in the analgesic area, includ-
`ing Sydney Archer, Louis Harris, Andrew Keats, and
`Everett May, from Small’s group.26 Highly active in
`the Committee, this network expanded in the late
`1960s to include U.K. chemist John Lewis, whose
`work would become crucial to bringing buprenor-
`phine to the attention of the ARC group.
`Through its historical role in relation to the
`CDAN (which became the Committee on Prob-
`lems of Drug Dependence [CPDD] in 1965), ARC
`researchers enjoyed constant access to new anal-
`gesic compounds. During the 1950s and 1960s,
`the Committee turned to studying the narcotic an-
`tagonists, including nalorphine;27–32 naltrexone;33
`LAAM (long-acting methadyl acetate), a long-
`acting derivative of methadone May synthesized un-
`der CPDD auspices;34 cyclazocine;35 phenazocine;36
`and pentazocine.37 Although dating from Commit-
`tee discussions in the 1940s, this route of experimen-
`tation intensified during the synthetic flood of the
`1950s. At the January 1953 CDAN meeting, Isbell
`had urged Henry K. Beecher and Louis Lasagna to
`run clinical trials of a nalorphine–morphine com-
`bination in order to establish nalorphine’s analgesic
`efficacy for post-operative pain. While these drugs
`were then being primarily studied as analgesics,38
`suggestions surfaced at Lexington that narcotic an-
`tagonists might help prevent relapse. Another path-
`way pursued from 1952 onward was May’s work
`building upon incomplete morphine molecules,
`which led to the production of phenylmorphans
`and benzomorphans (p. 676 in Ref. 40).39,40 By
`the mid-1960s, the Committee’s efforts to find a
`“chemopharmacological approach to the addiction
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`History and development of buprenorphine
`
`Campbell & Lovell
`
`problem” were focused on the narcotic antago-
`nists.40
`More than 30 years into its quest, the Committee
`was not overly optimistic about the chemophar-
`macological approach. Aware that heroin addic-
`tion could not be regarded solely as iatrogenic,
`the Committee did not think that a new medicine
`could effectively treat nonmedical addiction; rather,
`it focused on preventing potent new addictive
`compounds from being marketed. CDAN’s rele-
`vant historical touchstone was the “heroin mistake”
`stemming from initial claims that heroin was a
`“nonaddictive” alternative to morphine for analge-
`sia (p. 673).40 The “solution” to the heroin prob-
`lem had been framed as an alternative analgesic
`that would displace the need for opium production.
`Without the need for morphine or codeine (work
`was underway to replace codeine as an antitus-
`sive), the global opium supply could be controlled.
`However, by the 1960s, the Committee under-
`stood that its “chemical-pharmacological-clinical
`program” was founded upon an erroneous hy-
`pothesis concerning the potential ease of dissoci-
`ating the analgesic effects of morphine from the
`dependence-producing and respiratory-depressing
`effects (p. 674).40 The Committee turned toward
`narcotic antagonists upon the suggestion of Andrew
`Keats, hoping that this class of drugs would be clin-
`ically useful as analgesics.41
`Recognizing that if even one of the new antago-
`nists proved a sufficiently powerful analgesic with-
`out undue side effects, Eddy noted that it would
`still not “solve the addiction problem overnight
`(p. 679).40 Social and economic factors, he indi-
`cated, were paramount: “We shall still have the
`opium-producing countries. . . . We shall still have
`the established machinery for illicit production and
`distribution of heroin. . . [and] we shall still have
`the social and psychological forces that encourage
`potential addicts to dose themselves with drugs” (p.
`679).40 Eddy heralded the narcotic antagonists as
`progress in managing, rather than resolving, addic-
`tion problems: “We thought there might be found
`among the opiate antagonists one with the com-
`bination of antagonistic and analgesic properties
`which would give adequate clinical analgesia with-
`out excessive and disturbing side effects” (p. 679).40
`CDAN was not naive to nonmedical use but rather
`conceived of its role as acting within the national
`and international drug control apparatus to prevent
`
`new analgesics with potential to produce depen-
`dence from going onto the market.
`By the mid-1960s, the goals of the Committee
`(hereafter referred to as CPDD), underwent a con-
`ceptual shift toward finding a pharmacotherapy for
`addiction treatment and relapse prevention as a re-
`sult of Martin’s experimental work with the nar-
`cotic antagonists, which he felt were the best can-
`didate drugs for analgesics that did not produce
`dependence and for addiction therapeutics. Martin
`first studied cyclazocine, a long-acting, orally ef-
`fective narcotic antagonist developed at Sterling-
`Winthrop, as a “modality for preventing recidivism
`in ex-heroin addicts.”35 Martin set up a trial based
`on Wikler’s postulation that “conditioning”—the
`association of positive pharmacological effects and
`alleviation of withdrawal distress with specific envi-
`ronmental “cues” and social settings—played a role
`in perpetuating addiction.42 Wikler reasoned that
`it might be possible to “extinguish” associations by
`allowing addicts to inject an antagonist drug that
`would block the effect of the agonist drug. This hy-
`pothesis dovetailed with Martin’s observations that
`cyclazocine produced a different type of physical de-
`pendence than morphine.35 In suggesting that cy-
`clazocine might be efficacious as a new method for
`treating opiate addiction, Martin built upon find-
`ings that nalorphine, a narcotic antagonist his men-
`tor (Unna) had developed at Merck, competed with
`morphine at a receptor site but worked through a
`different mode of action. To make sense of this ob-
`servation, Martin introduced several concepts for
`which he became known: multiple opiate receptors’
`“competitive antagonism” at the receptor level, and
`“receptor dualism.”43–45 Another piece of the puzzle
`had to do with why the effects of abstinence should
`be so long lasting. Martin’s experiments conducted
`with Donald Jasinski, who joined the ARC in 1965
`from a postdoctoral position with Unna, led them to
`postulate a “secondary” or “protracted” abstinence
`syndrome that differed from the “explosive, early
`abstinence syndrome” tracked by Himmelsbach
`(p. 2).46 Tracing protracted abstinence, Martin and
`Jasinski found that its characteristics varied among
`individuals but fell within the range of normal phys-
`iological variables and were difficult to discern un-
`less researchers were in close proximity with sub-
`jects. Martin and Jewell W. Sloan observed negative
`attitudes in subjects in an 18-month study of pro-
`tracted abstinence and discussed their possible role
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`History and development of buprenorphine
`
`in relapse, with a rationale for using narcotic antag-
`onists in treatment of ambulatory narcotic addicts:
`“the view has been presented that the chronic ad-
`ministration of narcotic antagonists would prevent
`the exacerbation of protracted abstinence and may
`provide a circumstance whereby conditioned absti-
`nence and conditioned drug-seeking behavior could
`be extinguished.”47 While it was optimistic that fur-
`ther developments in neuroscience would yield a
`specific pharmacotherapy for addiction treatment
`and relapse prevention, Martin’s studies contained
`the germ of a shift in the addiction research com-
`munity toward addiction therapeutics.
`Relapse prevention had long been a problem for
`clinicians treating drug addicts. The idea that a phar-
`macotherapy could support relapse prevention by
`keeping patients in treatment helped change the goal
`from a nonaddictive analgesic to addiction thera-
`peutics. CPDD held that the “ability of an antagonist
`to suppress the satisfying response (euphoric effect)
`of an opiate (heroin)” could deter relapse; even more
`useful would be “prolongation of antagonistic ac-
`tion, either in an inherently longer-acting antagonist
`or a depot preparation” (p. 24).18 The Committee
`regarded an “antagonist-suppressant” as superior to
`agonist maintenance. In 1970, the Committee em-
`barked on an intensive search for a drug exhibiting
`prolonged antagonistic action. Naltrexone had been
`synthesized in 1963 at Endo Laboratories, a small
`pharmaceutical company with whom Martin con-
`sulted to develop the drug before DuPont purchased
`the company and dropped the project. Naltrexone
`was conceptualized as a “blockade” that fended off
`agonist access to receptor sites. While naltrexone
`would be approved as a pharmacologic adjunct to
`treatment for opioid addiction and alcohol in 1984,
`it never gained social acceptability among physi-
`cians or addicted patients despite appearing to be a
`pharmacologically perfect solution at the receptor
`level.48 Naltrexone was later touted as an anticrav-
`ing medication that had a “healing” effect on the
`endorphin system. CPDD also considered a novel
`combination in which oral opiates would be for-
`mulated with a small amount of naloxone to pre-
`vent diversion of morphine-like analgesics. In the
`mid-1970s, a search for the optimal components
`of such possible agonist–antagonist combinations
`commenced. By the early 1970s, however, the social
`and political context had changed in ways that facil-
`itated the shift toward addiction therapeutics that
`
`was occurring among the U.S. addiction research
`network.
`
`From safe analgesics
`to “chemotherapeutics”
`
`In 1964, Vincent Dole and Marie Nyswander ini-
`tiated a pilot research program on methadone
`maintenance at the Rockefeller Institute (later re-
`named the Rockefeller University).49 They cast
`methadone as a medication that had the social effect
`of “block[ing] the normal reactions of addicts to
`heroin and permit[ting] them to live as normal cit-
`izens in the community” (p. 304). 50 In 1966, Dole
`reported on the first 84 methadone maintenance
`patients to the Committee, which concluded that a
`“significant number of patients through methadone
`maintenance management have attained a reason-
`able degree of social rehabilitation. Their depen-
`dence has not been ameliorated, it has not been
`treated, it may have been augmented, but the patient
`and society have gained” (p. 114).18 The Commit-
`tee’s lukewarm reception of the methadone main-
`tenance pilot program and grudging acceptance of
`its social benefits was no surprise. The Commit-
`tee had never favored agonist maintenance. Debates
`over morphine maintenance had occurred in the
`1920s as part of the context in which the Com-
`mittee was formed. In the 1950s, there was an ac-
`tive national debate over the practice of morphine
`and/or heroin maintenance conducted conjointly
`by the American Bar Association and the Ameri-
`can Medical Association. At that time, the Com-
`mittee had opposed maintenance, aligning with the
`FBN against it. In the 1960s, the FBN was com-
`bined with the Bureau of Drug Abuse Control, an
`agency within the Department of Health, Educa-
`tion and Welfare, to form the Bureau of Narcotics
`and Dangerous Drugs (BNDD) in 1968, which
`in 1973 became the Drug Enforcement Adminis-
`tration (DEA). Committed to safeguarding public
`health against “unsafe analgesics,” the Committee
`aligned with the drug control apparatus in viewing
`methadone maintenance with skepticism. Similarly,
`the WHO Expert Committee on Drug Dependence
`considered methadone maintenance a research ap-
`proach but not an established treatment (p. 112).18
`Dole and Nyswander characterized such attitudes as
`those of a stodgy addiction research establishment
`opposed to methadone maintenance on political
`grounds.51
`
`Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c(cid:2) 2012 New York Academy of Sciences.
`
`129
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`TEVA PHARMACEUTICALS USA, INC. V. RB PHARMACEUTICALS LTD.
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`History and development of buprenorphine
`
`Campbell & Lovell
`
`New entrants to the field exemplified the attitude
`of experimentality then pervading drug treatment.
`Many embraced methadone maintenance despite
`acknowledging its limitations. For instance, Jerome
`H. Jaffe, who had spent a year working on the clini-
`cal side of the U.S. Narcotic Farm in the early 1960s,
`had heard Martin’s 1964 paper to the Committee
`on cyclazocine and theorized that narcotic antag-
`onists might work to prevent relapse, keep addicts
`in treatment, and reduce overdose events.52 In New
`York City, Jaffe and Leon Brill detoxed former heroin
`addicts unable to access methadone maintenance
`and put them on cyclazocine obtained from Sterling
`Winthrop. Although he ultimately switched patients
`to oral methadone due to ease of use compared to
`short-acting injectables, Jaffe considered the nar-
`cotic antagonists as having therapeutic potential
`for optimizing compliance and extending treatment
`duration.53 Jaffe spent six months with Dole and
`Nyswander learning the ropes of methadone main-
`tenance before he moved to Chicago to start a multi-
`modality drug treatment program, the Illinois Drug
`Abuse Program, which brought his work to the at-
`tention of the Nixon administration.
`The Nixon administration turned to methadone
`maintenance as a method for crime control and as
`a way to respond to concerns that a high percentage
`of heroin-addicted Vietnam veterans were returning
`opiate-addicted.54,55 In 1971, Nixon created the Spe-
`cial Action Office for Drug Abuse Prevention (SAO-
`DAP) and appointed Jaffe director. Despite concerns
`about methadone’s limitations, including the fre-
`quency of dosing, refusal, and refractory cases, Jaffe
`played a crucial role in expanding methadone main-
`tenance as a treatment modality in the United States.
`The Committee also shifted toward support for
`agonist maintenance in the 1970s and assisted
`in creating the first practice guidelines governing
`methadone maintenance, “Narcotics and Medical
`Practice,” which were issued in 1971 by a joint com-
`mittee composed of NAS/NRC committees, includ-
`ing CPDD, and the AMA Council on Mental Health.
`These guidelines stated that “methadone mainte-
`nance is not feasible in the office practice of pri-
`vate physicians” because they could not meet all of
`the therapeutic needs of such patients. Concerns
`about methadone diversion played a major part in
`the decision not to allow office-based methadone
`prescription, as physicians in private practice were
`considered incapable of “assur[ing] control against
`
`redistribution of the drug into illicit channels”
`(p. 114)18 Limiting diversion dominated discussions
`of methadone within the domestic drug control ap-
`paratus in the early 1970s.
`Despite the widespread support for methadone
`maintenance, there remained recognition of its lim-
`itations within the addiction research community.
`Research on alternative medications ranging from
`long-acting methadone to narcotic antagonists con-
`tinued even as methadone maintenanc