The history of the development of buprenorphine as...

Ann. N.Y. Acad. Sci. ISSN 0077-8923

ANNALS OF THE NEW YORK ACADEMY OF SCIENCESIssue: Addiction Reviews

The history of the development of buprenorphineas an addiction therapeutic

Nancy D. Campbell1 and Anne M. Lovell21Department of Science and Technology Studies, Rensselaer Polytechnic Institute, Troy, New York. 2Institut National de laSante et de la Recherche Medicale, Universite Paris Rene 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. [email protected]

This paper traces the early 21st century success of the agonist–antagonist buprenorphine and the combination drugbuprenorphine with naloxone within the broader quest to develop addiction therapeutics that began in the 1920sas the search for a nonaddictive analgesic. Drawing on archival research, document analysis, and interviews withcontemporary actors, this paper situates the social organization of laboratory-based and clinical research within thedomestic 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 fervorthat drove the champions of buprenorphine must be understood in relation to (1) the material work of research andpharmaceutical manufacturing; (2) the symbolic role of buprenorphine as a solution to numerous problems withaddiction 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 developnonaddicting analgesics

Addiction therapeutics arose within the historicalcontext of efforts to develop a nonaddicting anal-gesic that began in the United States in the early1920s. Early 20th century efforts to respond to the“opium problem,” through regulation and controlat the source of supply and to address public healthconcerns through innovation in the research lab-oratory set the stage for the gradual shift in re-searchers’ interests toward developing a treatmentfor addiction therapeutics. Diplomacy directed to-ward control of opium and its derivatives drovethe earliest interactions between the United Statesand the League of Nations. Policy elites consideredthe opium problem to be an acute threat to na-tional public health that could only be met throughinternational 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 Universitypharmacologist Reid Hunt urged the chair of theDivision of Medical Sciences (DMS) of the NationalAcademies of Science (NAS), National ResearchCouncil (NRC) to strengthen drug discovery, “thefield of medical research in which the United States ismost conspicuously backward.”3 This rationale laterled the NRC to adopt a committee formed to coor-dinate efforts to identify “non-habit forming opiatesand local anesthetics so that the use of opium andcocaine (the abuse of which almost balances the ben-efits) may be restricted or abolished.”3 Convened in1921 by the New York City Bureau of Social Hygiene,the Committee on Drug Addiction (CDA) under-took the search for morphine substitutes as a wayto attack the root of the “opium problem,” which itconsidered to be not “vicious” (nonmedical) con-sumption but medical use leading to addiction. TheCDA published The Opium Problem (1928), a heftycompendium reviewing 4,000 studies, which foundthat while the “consensus of opinion of the authors

doi: 10.1111/j.1749-6632.2011.06352.x124 Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c© 2012 New York Academy of Sciences.

Campbell & Lovell History and development of buprenorphine

reviewed is that the majority of cases of chronicopium intoxication lies in the therapeutic use of thedrug,” there was rising heroin use for “purposes ofdissipation” (p. 13).4 Committee sponsorship wasassumed by the Rockefeller Foundation from 1932to 1939, after which the CDA became part of theNAS/NRC and was relatively self-sustaining throughmodest contributions from the pharmaceutical in-dustry and National Institute of Health (NIH; in1949 renamed National Institutes of Health). TheCommittee undertook chemical dissection of themorphine molecule, seeking to dissociate analge-sia from addiction liability and emphasizing directmanipulation of the morphine molecule to developnonaddictive substitutes for each known medicaluse of morphine.

The solution to the “opium problem” was firstsought at the laboratory bench at a time when theUnited States was becoming a major player withinthe evolving international drug control framework.For such a narrowly tailored goal to be understoodas meeting a broad social problem of unclear etiol-ogy, it had to be translated into a fundable researchprogram. Reliable methods to test compounds inanimals and human beings had to be developedand validated. In the CDA’s first decade, some150 compounds were produced and evaluated; allbut one—Metopon (5-methylhydromorphone)—demonstrated the elusiveness of the goal.5

Although iatrogenic addiction had declined withchanges in medical practice,6 physicians remainedthe chief vectors of opiate addiction in the early20th century. The Committee’s goals dovetailedwith an American Medical Association (AMA) re-form agenda to “reduce indications for opiates toan irreducible minimum” (p. 95).7 CDA leader-ship supported scientific investigation of narcotics,including analyses of the chemical and biologicalliterature on addiction alkaloids; formulation ofrules and regulations for legitimate use of alkaloidshaving addiction properties, and education of physi-cians and the public about these rules; and “replace-ment of all present use of addiction alkaloids bysubstitutes having no addiction properties” (p. 11)(emphasis ours).8

Morphine was the Committee’s target becauseit had numerous specific uses in clinical prac-tice, many of which, according to the first com-mittee report, could already be satisfied by otherdrugs. 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 replacethe legitimate uses of morphine with a number ofsubstitutes. . . [If it is. . .] possible to substitutefor all legitimate uses of morphine other chemicalcompounds without addiction properties, it shouldrender morphine an unnecessary commodity in in-ternational commerce” (p. 11).9 White noted that“setting up a machinery for a specific purpose; thatis, of an attempt at a solution of a definite problemof international importance” was new for the NRCDivison of Medical Sciences. The Committee wascharged with reducing legitimate use by decreasingphysician’s prescriptions and proprietary remediescontaining narcotics, replacing each use of habit-forming drugs with a substance that was not habit-forming but capable of producing the medicinalaction required, and reducing to a minimum thelegitimate production of alkaloids and thus less-ening the necessity for controls.10 The Committeewas also asked to conduct public education semi-nars on the indispensable uses of morphine, to seekto prepare by synthesis and analysis compoundswithout addiction fractions, and to study the ef-fects of these compounds in animals and later inhuman therapy. White arranged with Morris Fish-bein, editor of the Journal of the American Med-ical Association, to publish the Committee’s rulesand regulations governing morphine prescription,which was released as The Indispensable Uses ofNarcotics.11

The Committee’s research program was a highlyorganized, centrally orchestrated effort—one of thefirst scientific collaborations that focused the U.S.government scientific resources on solving a socialproblem. Cooperation between CDA and the U.S.Public Health Service (PHS) was secured by strate-gic appointments. Clinical studies commenced in1933 at the federal penitentiary in Fort Leaven-worth, Kansas. However, in 1929 the U.S. Congresspassed the Porter Bill, authorizing construction of“narcotic farms” to rehabilitate addicts. When thefirst U.S. Narcotic Farm opened in Lexington, Ken-tucky, in 1935, a tiny research laboratory was housedwithin the 1,500-bed institution. In May 1938, thePHS broadened the NIH role in the Committee byestablishing a chemotherapy unit consisting of sev-eral chemists who had been associated with CDA,including Nathan B. Eddy, Erich Mosettig, EverettL. May, and Lyndon F. Small. The Committee also

Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c© 2012 New York Academy of Sciences. 125

History and development of buprenorphine Campbell & Lovell

had at its disposal a PHS clinical researcher, CliftonK. Himmelsbach, who had worked with Eddyto pioneer the “morphine substitution technique”developed to compare the addiction liability of novelcompounds to morphine. The Himmelsbach tech-nique was based on the principle that, “A substancewhich will support and maintain the ‘addicted state’is essentially addictive in and of itself” (p. 26).12

Research objectives included “new treatment andsubstitution techniques, intensive study of physico-chemical, psychiatric, and psychological changes re-sulting from single therapeutic and repeated dosesof morphine in the non-tolerant individual, dur-ing stabilized addiction, and in the post-addictionstate” (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 cyclesof tolerance, addiction, and withdrawal or “absti-nence,” Himmelsbach generated hourly and dailypoint scores that yielded a method for calculatingthe intensity of abstinence and predicting its course.He had previously gained insight into techniquesfor quantitatively comparing degrees of “addictive-ness” through study of desomorphine and meto-pon, a drug developed by Small and marketed forchronic pain until the early 1950s. Metopon wasconsidered proof of concept for the idea upon whichthe Committee was configured—the dissociationof analgesic activity from the undesirable tendencyto 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 IIto produce methadone, the synthetic analgesic re-covered by the Allies during a U.S. Department ofCommerce investigation of German wartime indus-tries.17 During the war, the Committee’s operationswere suspended, but methadone came to the Com-mittee’s attention just as it resumed operation afterthe war’s end (p. 52).18

Renamed the Committee on Drug Addiction andNarcotics (CDAN), the Committee’s first postwarmeeting was held at the NRC in 1947. Attendingwere Isaac Starr, the newly appointed chair; Harry J.Anslinger, chief of the Federal Bureau of Narcotics(FBN); Raymond N. Bieter, Head of Pharmacologyat University of Minnesota Medical School; DaleC. Cameron, later chief of the Drug Dependence

Section of the World Health Organization (WHO);Maurice H. Seevers, whose University of Michiganlaboratory the committee had designated for animaltesting; Eddy and Small from NIH; and representa-tives of the Armed Services, FDA, AMA TherapeuticTrials Committee, and the American Drug Man-ufacturer’s Association. Amidon (methadone) wasone of the postwar committee’s first considerations,as several pharmaceutical firms were interested inmanufacturing methadone or derivatives. NathanB. Eddy, who had worked with the committee since1930, proposed that CDAN serve as a clearinghouseto which manufacturers of analgesic drugs submitinformation 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 drugswould be subjected. At the first postwar CDANmeeting, Anslinger gained the Committee’s ap-proval of a draft protocol to bring synthetic drugsunder international control. Whereas the opium-producing countries of the developing world viewedthe new synthetics as dangerous and difficult to con-trol, the United States feared it could not stem theflow of opiates from producing countries.1 CDANprovided recommendations concerning levels ofcontrol 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 “onDrugs Liable to Produce Addiction”) to recommendlevels of control to regulatory bodies. Along with theWHO section that it advised, the Expert Commit-tee rapidly forged a principle of balancing medicalutility against the social risks of abuse. The inter-national treaties, the Single Convention of 1961,and Psychotropic Convention of 1971 reflected theview that the more medically useful a drug, the lessstrict 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 aclass, as the drugs of natural origin.”20 Eddy playeda leadership role in the Expert Committee from itsfounding until his death. CDAN members served onit and supplied data to it, shaping its drug definitionsand criteria for control. The Expert Committee, forexample, depended “in large measure upon receiptof information” from American research, funneledthrough CDAN (p. 11).18

126 Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c© 2012 New York Academy of Sciences.


The Addiction Research Center (ARC), as the lab-oratory at Lexington was called after 1948 whenit joined the newly formed National Institute ofMental Health (NIMH), studied methadone inhuman subjects, finding that it produced a milder,more prolonged version of the abstinence syndromethan other opiates, according to the Himmelsbachscale. 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 opposedusing methadone for maintenance given the re-sults of studies he and Abraham Wikler conductedon former morphine and/or heroin addicts in thelate 1940s indicating that the subjects expressedincreased satisfaction as dosage increased.21 Theyconcluded that “narcotic drug addicts would abusemethadone and would become habituated to it if itwere 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 thatmethadone would present a potentially serious pub-lic health problem if manufacture and distributionwere not controlled.22

Despite controls, methadone was used as an“office-based” addiction treatment by a handfulof physicians who prescribed it in the 1950s; theNew York State Department of Mental Health ranan informal methadone maintenance program in1959.23 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 the1950s, the Committee’s drug development hopesfastened upon another class of drugs—the narcoticantagonists—as an alternative to agonists like mor-phine and methadone. A spirit of experimentalitypermeated the organizations and research networksthrough which addiction researchers and cliniciansthen worked.

The mid-20th century project to developnarcotic antagonists as “safe analgesics”

In 1963, Isbell and Wikler retired, handing over theARC to neuropharmacologist William R. Martin,

who joined the group in 1957. Martin studied theunderlying neural mechanisms of addiction, andhad immersed himself in Himmelsbach’s early find-ings, becoming convinced that tolerance was an ex-tremely complex neuronal phenomenon. He set outto 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 ofthe phenomena of early and protracted abstinence”(p. 108).24 Martin, a physician and World War IIArmy veteran, had prepared a doctorate in neu-ropharmacology under Klaus R. Unna, who, whileworking for Merck, discovered that nalorphine, anarcotic antagonist, could “prevent or abolish theaction of morphine.”25 Martin worked in a highlyoriginal and theoretical way with a close-knit circleof chemists innovating in the analgesic area, includ-ing Sydney Archer, Louis Harris, Andrew Keats, andEverett May, from Small’s group.26 Highly active inthe Committee, this network expanded in the late1960s to include U.K. chemist John Lewis, whosework would become crucial to bringing buprenor-phine to the attention of the ARC group.

Through its historical role in relation to theCDAN (which became the Committee on Prob-lems of Drug Dependence [CPDD] in 1965), ARCresearchers 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 the1950s. At the January 1953 CDAN meeting, Isbellhad urged Henry K. Beecher and Louis Lasagna torun clinical trials of a nalorphine–morphine com-bination in order to establish nalorphine’s analgesicefficacy for post-operative pain. While these drugswere 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 workbuilding upon incomplete morphine molecules,which led to the production of phenylmorphansand benzomorphans (p. 676 in Ref. 40).39,40 Bythe mid-1960s, the Committee’s efforts to find a“chemopharmacological approach to the addiction



problem” were focused on the narcotic antago-nists.40

More than 30 years into its quest, the Committeewas 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 medicinecould effectively treat nonmedical addiction; rather,it focused on preventing potent new addictivecompounds 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 analgesicthat would displace the need for opium production.Without the need for morphine or codeine (workwas 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-clinicalprogram” was founded upon an erroneous hy-pothesis concerning the potential ease of dissoci-ating the analgesic effects of morphine from thedependence-producing and respiratory-depressingeffects (p. 674).40 The Committee turned towardnarcotic antagonists upon the suggestion of AndrewKeats, 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 wouldstill not “solve the addiction problem overnight(p. 679).40 Social and economic factors, he indi-cated, were paramount: “We shall still have theopium-producing countries. . . . We shall still havethe established machinery for illicit production anddistribution of heroin. . . [and] we shall still havethe social and psychological forces that encouragepotential addicts to dose themselves with drugs” (p.679).40 Eddy heralded the narcotic antagonists asprogress in managing, rather than resolving, addic-tion problems: “We thought there might be foundamong the opiate antagonists one with the com-bination of antagonistic and analgesic propertieswhich would give adequate clinical analgesia with-out excessive and disturbing side effects” (p. 679).40

CDAN was not naive to nonmedical use but ratherconceived of its role as acting within the nationaland 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 foraddiction 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 producedependence and for addiction therapeutics. Martinfirst studied cyclazocine, a long-acting, orally ef-fective narcotic antagonist developed at Sterling-Winthrop, as a “modality for preventing recidivismin ex-heroin addicts.”35 Martin set up a trial basedon Wikler’s postulation that “conditioning”—theassociation of positive pharmacological effects andalleviation of withdrawal distress with specific envi-ronmental “cues” and social settings—played a rolein perpetuating addiction.42 Wikler reasoned thatit might be possible to “extinguish” associations byallowing addicts to inject an antagonist drug thatwould block the effect of the agonist drug. This hy-pothesis dovetailed with Martin’s observations thatcyclazocine produced a different type of physical de-pendence than morphine.35 In suggesting that cy-clazocine might be efficacious as a new method fortreating opiate addiction, Martin built upon find-ings that nalorphine, a narcotic antagonist his men-tor (Unna) had developed at Merck, competed withmorphine at a receptor site but worked through adifferent mode of action. To make sense of this ob-servation, Martin introduced several concepts forwhich he became known: multiple opiate receptors’“competitive antagonism” at the receptor level, and“receptor dualism.”43–45 Another piece of the puzzlehad to do with why the effects of abstinence shouldbe so long lasting. Martin’s experiments conductedwith Donald Jasinski, who joined the ARC in 1965from a postdoctoral position with Unna, led them topostulate a “secondary” or “protracted” abstinencesyndrome that differed from the “explosive, earlyabstinence syndrome” tracked by Himmelsbach(p. 2).46 Tracing protracted abstinence, Martin andJasinski found that its characteristics varied amongindividuals 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 negativeattitudes in subjects in an 18-month study of pro-tracted abstinence and discussed their possible role



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 preventthe exacerbation of protracted abstinence and mayprovide a circumstance whereby conditioned absti-nence and conditioned drug-seeking behavior couldbe extinguished.”47 While it was optimistic that fur-ther developments in neuroscience would yield aspecific pharmacotherapy for addiction treatmentand relapse prevention, Martin’s studies containedthe germ of a shift in the addiction research com-munity toward addiction therapeutics.

Relapse prevention had long been a problem forclinicians treating drug addicts. The idea that a phar-macotherapy could support relapse prevention bykeeping patients in treatment helped change the goalfrom a nonaddictive analgesic to addiction thera-peutics. CPDD held that the “ability of an antagonistto suppress the satisfying response (euphoric effect)of an opiate (heroin)” could deter relapse; even moreuseful would be “prolongation of antagonistic ac-tion, either in an inherently longer-acting antagonistor a depot preparation” (p. 24).18 The Committeeregarded an “antagonist-suppressant” as superior toagonist maintenance. In 1970, the Committee em-barked on an intensive search for a drug exhibitingprolonged antagonistic action. Naltrexone had beensynthesized in 1963 at Endo Laboratories, a smallpharmaceutical company with whom Martin con-sulted to develop the drug before DuPont purchasedthe company and dropped the project. Naltrexonewas conceptualized as a “blockade” that fended offagonist access to receptor sites. While naltrexonewould be approved as a pharmacologic adjunct totreatment for opioid addiction and alcohol in 1984,it never gained social acceptability among physi-cians or addicted patients despite appearing to be apharmacologically perfect solution at the receptorlevel.48 Naltrexone was later touted as an anticrav-ing medication that had a “healing” effect on theendorphin system. CPDD also considered a novelcombination in which oral opiates would be for-mulated with a small amount of naloxone to pre-vent diversion of morphine-like analgesics. In themid-1970s, a search for the optimal componentsof such possible agonist–antagonist combinationscommenced. By the early 1970s, however, the socialand political context had changed in ways that facil-itated the shift toward addiction therapeutics that

was occurring among the U.S. addiction researchnetwork.

From safe analgesicsto “chemotherapeutics”

In 1964, Vincent Dole and Marie Nyswander ini-tiated a pilot research program on methadonemaintenance at the Rockefeller Institute (later re-named the Rockefeller University).49 They castmethadone as a medication that had the social effectof “block[ing] the normal reactions of addicts toheroin and permit[ting] them to live as normal cit-izens in the community” (p. 304). 50 In 1966, Dolereported on the first 84 methadone maintenancepatients to the Committee, which concluded that a“significant number of patients through methadonemaintenance management have attained a reason-able degree of social rehabilitation. Their depen-dence has not been ameliorated, it has not beentreated, it may have been augmented, but the patientand society have gained” (p. 114).18 The Commit-tee’s lukewarm reception of the methadone main-tenance pilot program and grudging acceptance ofits social benefits was no surprise. The Commit-tee had never favored agonist maintenance. Debatesover morphine maintenance had occurred in the1920s 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 morphineand/or heroin maintenance conducted conjointlyby the American Bar Association and the Ameri-can Medical Association. At that time, the Com-mittee had opposed maintenance, aligning with theFBN against it. In the 1960s, the FBN was com-bined with the Bureau of Drug Abuse Control, anagency within the Department of Health, Educa-tion and Welfare, to form the Bureau of Narcoticsand Dangerous Drugs (BNDD) in 1968, whichin 1973 became the Drug Enforcement Adminis-tration (DEA). Committed to safeguarding publichealth against “unsafe analgesics,” the Committeealigned with the drug control apparatus in viewingmethadone maintenance with skepticism. Similarly,the WHO Expert Committee on Drug Dependenceconsidered methadone maintenance a research ap-proach but not an established treatment (p. 112).18

Dole and Nyswander characterized such attitudes asthose of a stodgy addiction research establishmentopposed to methadone maintenance on politicalgrounds.51



New entrants to the field exemplified the attitudeof experimentality then pervading drug treatment.Many embraced methadone maintenance despiteacknowledging its limitations. For instance, JeromeH. 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 Committeeon cyclazocine and theorized that narcotic antag-onists might work to prevent relapse, keep addictsin treatment, and reduce overdose events.52 In NewYork City, Jaffe and Leon Brill detoxed former heroinaddicts unable to access methadone maintenanceand put them on cyclazocine obtained from SterlingWinthrop. Although he ultimately switched patientsto oral methadone due to ease of use compared toshort-acting injectables, Jaffe considered the nar-cotic antagonists as having therapeutic potentialfor optimizing compliance and extending treatmentduration.53 Jaffe spent six months with Dole andNyswander learning the ropes of methadone main-tenance before he moved to Chicago to start a multi-modality drug treatment program, the Illinois DrugAbuse Program, which brought his work to the at-tention of the Nixon administration.

The Nixon administration turned to methadonemaintenance as a method for crime control and asa way to respond to concerns that a high percentageof heroin-addicted Vietnam veterans were returningopiate-addicted.54,55 In 1971, Nixon created the Spe-cial Action Office for Drug Abuse Prevention (SAO-DAP) and appointed Jaffe director. Despite concernsabout methadone’s limitations, including the fre-quency of dosing, refusal, and refractory cases, Jaffeplayed a crucial role in expanding methadone main-tenance as a treatment modality in the United States.

The Committee also shifted toward support foragonist maintenance in the 1970s and assistedin creating the first practice guidelines governingmethadone maintenance, “Narcotics and MedicalPractice,” 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 ofthe therapeutic needs of such patients. Concernsabout methadone diversion played a major part inthe decision not to allow office-based methadoneprescription, as physicians in private practice wereconsidered incapable of “assur[ing] control against

redistribution of the drug into illicit channels”(p. 114)18 Limiting diversion dominated discussionsof methadone within the domestic drug control ap-paratus in the early 1970s.

Despite the widespread support for methadonemaintenance, there remained recognition of its lim-itations within the addiction research community.Research on alternative medications ranging fromlong-acting methadone to narcotic antagonists con-tinued even as methadone maintenance expanded.Research on long-acting methadone (LAAM) hadbeen sponsored by the NIMH Division of Nar-cotic Addiction and Drug Abuse (DNADA) in thelate 1960s.56 Understood to lack abuse liability,LAAM and the narcotic antagonists were thoughtless likely candidates for diversion. Methadone treat-ment centers, with the notable exception of Dole andNyswander’s program, operated under relatively in-formal FDA-issued Investigational New Drug (IND)designations, until SAODAP and FDA jointly im-posed formal regulations to create a “hybrid IND-NDA (New Drug Application) that acknowledgedthe safety and efficacy of methadone maintenanceas a treatment but imposed a number of conditionson how it could be used,” in 1973 (p. S5),57 resultingin a system of stand-alone clinics and restriction ofmethadone in private practice. In 1974, Congressbecame concerned with methadone diversion andamended the Controlled Substances Act (CSA), in1970. to give DEA considerable powers despite theinception of the National Institute on Drug Abuse(NIDA) and sunset of SAODAP in 1973. Many clin-icians, including Dole and Jaffe, came to view themethadone regulations as government interferencewith the practice of medicine.52 The restrictive cli-mate had led SAODAP to prioritize developmentof narcotic antagonists; The White House officesought to contract with CPDD to conduct PhaseIII studies on narcotic antagonists.58 While bothorganizations agreed that it was desirable to movebeyond methadone maintenance in the addictiontherapeutics arena, the organizational complexitiesof arranging for CPDD to run a SAODAP-initiatedNarcotic Antagonist Project delayed the process.

Relapse was SAODAP’s target. Primary sourcesindicate that the push to develop narcotic antag-onists as addiction treatment drugs was drivenby a search for a viable alternative to methadonemaintenance.58–59 Narcotic antagonists were sug-gested as a “therapeutic maintenance agent for



opiate-dependent individuals”59 on the assumptionthat the high recidivism rate among opiate addictsresulted from a “biochemical abnormality inducedby the prolonged use of a narcotic” or a continuing“psychological dependence” that could be blockedby an antagonist long enough for the behavior tobe “decondition[ed]” (p. 1).59 Long-acting antago-nists were ruled out because of “considerable ago-nist activity,” but a few series of new compoundswere being shown to have strong antagonist prop-erties with little or no agonist activity (p. 2).59 Foursuch compounds that appeared “very promising”to SAODAP officials were almost through the ani-mal and human testing process for safety and toxi-city. Although these compounds were ready to en-ter large-scale, Phase III human trials, the NationalAcademy made it clear to SAODAP that it would notallow CPDD to assume responsibility for drug de-velopment or clinical trials management despite thesocial and political climate surrounding methadonein the early to mid-1970s making narcotic antago-nists look comparatively hassle-free. The SAODAPdecision to develop narcotic antagonists was basedon their potential clinical value for treating patientsunwilling or unable to participate in methadonemaintenance, including “young users and early usersinappropriate as maintenance subjects.”59 Despitethe CPDD’s sustained interest in the developmentof antagonists for treatment of narcotics addiction,NAS president Philip Handler declined to allowCPDD to assume a managerial role in conductingclinical trials. Instead he created a new Committeefor the Evaluation of Narcotic Antagonists (CENA),which conducted a study of naltrexone under NASauspices.60

The National Academy of Sciences reorganized itscommittee structure in 1975, leading to the termi-nation of CPDD as an NRC committee. While theCommittee had played a unique and invaluable roleduring its long and productive existence, the emer-gence of drug abuse as a national issue of majorimportance had attracted many new organizationswith greater resources that overshadowed CPDD’sonce unique capabilities.61

Other uncertainties also pervaded the addictionresearch arena. The Federal Bureau of Prisons de-cided in April 1976 to phase out all participationof federal prisoners in clinical trials and shut downthe ARC’s prison recruitment channel. When Mar-tin traveled to Washington, DC, to defend addic-

tion research, his rationale for continued investmentwas the compelling need to develop alternatives tomethadone (agonist) maintenance. Still at the ARCin Lexington, Jasinski turned his scientific attentionto addiction therapeutics. Both researchers pointedto buprenorphine as a sign of progress: “Recogniz-ing the possibility of partial agonists of the morphinetype such as profadol, propiram and buprenorphineand evolving methods for identifying them haveopened the possibility of a narcotic analgesic whoseagonistic activity will be great enough to fulfill clin-ical expectation but not produce dangerous side ef-fects or a clinically significant degree of physicaldependence.”62 The fervor that developed amongbuprenorphine’s champions must be understood inrelation to the symbolic role the drug played in jus-tifying continued federal investment in addictionresearch.

Building on SAODAP’s narcotic antagonistproject, NIDA published a series of research mono-graphs on drug development in the mid-1970s.63–65

One monograph named naltrexone as the mostpromising of these “new” methods.65 The editorsintroduced NIDA’s “newly established drug devel-opment program,” first applying the term “orphandrug” to addiction treatment: “With increasing fre-quency, Federal agencies are being called upon toevaluate and develop new drugs and treatments fora wide variety of diseases and related conditions.The so-called ‘orphan’ drugs, or drugs of little orlimited commercial value, are being shunned by thepharmaceutical industry, due primarily to the ever-increasing developmental costs and risks associatedwith new drugs. Thus, within the Public Health Ser-vice, a drug development effort has emerged to fillthis void.”65 Orphan drug designation would be-come key to buprenorphine’s career as an addictiontherapeutic.

Buprenorphine’s career as an addictiontherapeutic

Buprenorphine was discovered in 1966, at the re-search labs of a home products company, Reckitt& Colman (hereafter Reckitts), in Hull, England.Working for the company was Oxford-trainedchemist John Lewis, a doctoral student of the Nobelprizewinning organic chemist, Sir Robert Robinson,who elucidated the active structure of morphine in1925. Kenneth Bentley, father of the “Bentley com-pounds,” was a postdoctoral researcher at Oxford



when Lewis did his graduate studies there. Bent-ley went on to McFarlan Smith in Edinburgh, thenthe main U.K. producers of opium alkaloids. In1958, the company entered into joint venture withReckitts (1958–1963) to develop over-the-counteranalgesics. According to Lewis,66 Bentley laid the“chemical foundations” for the Reckitts opioid drugdevelopment project in the 1950s. He believedthat “opioids with structures substantially morecomplex than morphine could selectively retain thedesirable actions whilst shedding the undesirableside effects,” a vision convergent with that of Eddyand the Committee. In 1963, Reckitts took over thejoint project, after McFarlan Smith was absorbedinto another company.67 Reckitts developed two un-successful opiates (etorpine, a potent �-agonist, andits antagonist),67 before putting buprenorphine intoPhase 1 studies on “committed volunteers” includ-ing Lewis himself,66 in the late 1960s.

Reckitts supplied buprenorphine to the ARC re-searchers in Lexington throughout the 1970s, andARC’s Jasinski consulted regularly with the com-pany.67 In 1972, Lewis disclosed buprenorphine’spharmacological profile at the annual CPDD meet-ing. While an immediate impact seems not to haveoccurred, Lexington researchers went on to studybuprenorphine as a potential addiction treatmentdrug because of its combination of analgesic (ago-nist) and antagonist properties. According to Lewis,“The story of the development of buprenorphine asan addict treatment” [emphasis ours] began in 1975,when Jasinski countered growing opposition to us-ing prisoners as clinical research subjects by arguingthat many prisoners were addicts and the pharma-cology of buprenorphine made it such an “attrac-tive candidate” as a treatment for opiate dependencethat its human abuse potential was in urgent need ofstudy.66 Jasinski et al. announced the addiction ther-apeutics potential of buprenorphine in a landmarkpaper in 1978.68

In 1979, Jasinski classified the narcotic antago-nists into three groups: (1) compounds that pro-duced agonistic effects that do not resemble mor-phine (nalorphine and cyclazocine), (2) compoundsthat do not produce agonistic effects (naloxone andnaltrexone), and (3) antagonists that produce ago-nistic effects that resemble those of morphine be-cause they are also partial agonists of morphine.By then, six category 1 narcotic antagonists hadbeen introduced as analgesics with low abuse po-

tential. According to Jasinski’s scheme, propiramand buprenorphine fit category 3.69 Interest shiftedto these “partial agonists of the morphine type,”which did not constitute a homogenous class dueto their intrinsically different capacities for pro-ducing euphoria, sedation, and psychotomimeticeffects.70

At annual CPDD meetings from 1975 on, Jasinskisuggested that buprenorphine usefully combinedthe characteristics of methadone with those of a pureopiate antagonist and effectively blocked morphine(p. 5).71 Jasinski singled out buprenorphine as hav-ing an “especially unique pharmacology in man” be-cause it produced “very little physical dependence”even with chronic administration (p. 290S).69 Citinghis 1978 study, he speculated that buprenorphine“would not only have a therapeutic application asan analgesic of low abuse potential but also as anew type of drug treatment of narcotic addiction.”69

Jasinski heralded buprenorphine’s unique potentialbecause it alone produced long-lasting “changes infeelings that are acceptable to addicts,” and was“less toxic than methadone,”70 declaring that thecommittee’s 50-year project to “potentially utilizenarcotics therapeutically to both relieve pain andtreat addiction without the production of physi-cal dependence” had yielded buprenorphine, which“appears to have the advantage of both methadoneand naltrexone but without the major disadvan-tage of each” (p. 85).70 For at least some parties,the search had funneled down to one candidatedrug.

Given the enthusiasm for buprenorphine withinthe addiction research network, its meandering pathto market as an addiction therapy is puzzling. Whydid it take almost three decades after Martin andJasinski’s recognition of buprenorphine’s therapeu-tic potential for it to be approved by the FDA fortreatment of opioid dependence? Buprenorphinefaced many hurdles, including scheduling issues;reluctance of pharmaceutical companies to takeon addiction medicaments; fall-out from experi-ment, diversion, and abuse of its analgesic form71;and still restrictive addiction treatment systems. Aswith methadone maintenance, many within the ad-diction research enterprise had become convincedof buprenorphine’s uniqueness as an opioid ad-diction treatment. However, the social and politi-cal context was quite different, given the maturityof the drug regulatory apparatus, the changing



knowledge base in the field, and what hadbeen learned from the experience of methadonemaintenance delivery through a stand-aloneclinic system detached from office-based medicalpractice.

In 1979, following the ban on use of federalprisoners as research subjects, NIDA had movedthe ARC’s Clinical Research Program, now underthe direction of Jasinski, to the medical campusof The Johns Hopkins University (JHU) in Balti-more, Maryland; the preclinical program followedin 1981. The JHU site was chosen partly becauseBaltimore provided a suitable source of researchsubjects: inner-city heroin addicts.72–73 Addictionresearchers considered it unethical and unwise tocarry out research involving addictive substances onpeople who were not or had not been addicted. Fur-thermore, residential laboratories were necessary. AsMartin told an interviewer in 1980, he “would neverconduct an experiment in which I chronically ad-ministered a potentially addicting drug to a patientwho could leave the setting at will.”74

The Baltimore buprenorphine studies, conductedby the JHU Behavioral Pharmacology Research Unit(BPRU) headed by George Bigelow, grew out of theARC’s move to the Hopkins campus, which broughtbuprenorphine to Baltimore. Bigelow recalled thatthe ARC brought with them “connections to newdrugs, the pharmaceutical industry, and the med-ications development field, in a way that we hadnot really had before. In particular, they brought ac-cess to buprenorphine, which was difficult to makeand supplied only by Reckitts. Don Jasinski had beenworking with buprenorphine and had published thefirst paper suggesting it could be useful in addictiontreatment.”75 The BPRU collaborated early on withARC researchers, including on a study evaluatingbuprenorphine in comparison to methadone76 andanother evaluating a range of doses of buprenor-phine in an opioid challenge.77 Bigelow recalledthat these “mark[ed] the primary beginnings ofusing that methodology and incorporating [ARC]methods in our studies.”75 One pharmacologist,R. Ed Johnson, who had compounded buprenor-phine for Martin and Jasinski’s studies while a phar-macist in Lexington, assisted Jasinski in moving theARC’s Clinical Research Program from Lexingtonto Baltimore in 1979. While working at the ARC(renamed the NIDA Intramural Research Programin the 1990s), Johnson served as lead investigator on

several development studies of buprenorphine andpublished results from the first pivotal clinical trialof buprenorphine in 1992.78 Following his retire-ment from the U.S. Public Health Service in 1991,he joined the faculty of the BPRU at Johns Hopkinswhere he continued to conduct clinical trials withbuprenorphine funded by NIDA79–80 and dedicatedhis scientific career to bringing buprenorphine tomarket as an addiction treatment.

Congress charged NIDA with assuming respon-sibility for new addiction treatment methods inthe early 1980s. CPDD continued meeting annu-ally, although its drug development and evaluationprograms shrank. In February 1983, CPDD held asymposium on agonist-antagonists that included areview of buprenorphine presented by John Lewis.At this symposium, Martin attributed his recogni-tion of the possibility of developing a “less toxic,less addicting drug by developing a partial agonistof the morphine type” to the studies he had con-ducted with Jasinski on buprenorphine in the dog,which laid the foundation for understanding that“these antagonists do things that morphine does notdo . . . [they are] much safer drugs . . . their abusepotentiality is less . . . they have a unique pharma-cology that probably provides us hints about wherewe can go further in the future” (p. 84).81 Jasinskispoke to buprenorphine’s advantages over naltrex-one, noting that his subjects liked buprenorphinebetter, and “felt comfortable on it. The inductionof a feeling state that they found salient followingbuprenorphine was certainly there. . . Most of oursubjects told us that it was, in fact, the most reinforc-ing drug that they had ever used” (p. 95).81 Despitethis caution, buprenorphine was offered as a “safeand effective mode of pharmacotherapy for heroinaddiction.”81–82

By 1985, injectable buprenorphine had beenmarketed for analgesic applications in 29 coun-tries and the sublingual tablet in 16 countries. Inthe United Kingdom, Reckitts had launched in-jectable buprenorphine for severe pain in 1978, withthe sublingual analgesic following in 1982. It li-censed Norwich–Eaton to distribute buprenorphinehydrochloride (Buprenex) in the United States,where the analgesic was launched in 1985, afterFDA approval. However, scheduling incited lengthystruggles. Scheduling was still (and remains) anartifact of almost a century of domestic drugpolicy culminating in the 1970 U.S. Controlled



Substances Act (CSA) and, internationally, the Sin-gle Convention of 1961 and Psychotropic Con-vention of 1971. Domestic and international con-ventions are based on proving pharmacologicalequivalence. The classical antagonists, such asnaloxone, naltrexone, and nalorphine, catalyzedconsiderable arguments about whether they re-ally fit the definition of dependence-producingdrugs. Charles O’Keeffe, a former Clinton ad-visor and later President of the U.S. companyReckitts Benckiser Pharmaceuticals, has explained,“You had to jointly defend the class of drugs, tokeep the agonist/antagonists where they were.”83

The DEA followed the international conventionscheduling, even if technically they could dootherwise. Internationally, buprenorphine propo-nents fought to put buprenorphine under theless restrictive Psychotropic Convention, arguingthat pharmacological effects and dependence lia-bility were distinctly different. Domestically, theDEA tried to reschedule buprenorphine threetimes.

But the shift from research to industrial drugdevelopment for addiction treatment took off atthe intersection of two trajectories: formal inter-est on the part of NIDA and a change of orien-tation within Reckitts. In 1989, the U.S. Congressmandated that a Medications Development Pro-gram be established in NIDA. The following year,NIDA established the Medications DevelopmentDivision (MDD) to develop close working rela-tionships between academia, the pharmaceuticalindustry, and government agencies, including theFDA, so as to develop and evaluate addiction treat-ment medications to the point that they couldgo through the FDA approval process. An In-stitute of Medicine (IOM) report identified re-lapse prevention as the proper focal point forthe MDD, but noted that the basic knowledgeabout the pathophysiology of protracted abstinenceand conditioned withdrawal remained rudimentary(p. 48).84 One of the MDD’s first priorities was toget LAAM approved for an addiction treatment in-dication. This objective was accomplished in 1993and LAAM was launched in the United States in1994. In 1993, MDD also approached Reckitts aboutformalizing their already existing mutual interestin developing buprenorphine for addiction treat-ment. NIDA was interested in buprenorphine byitself and in combination with naloxone (to prevent

diversion). Reckitts was NIDA’s obvious choice for aCooperative Research and Development Agreement(CRADA), as another company would have had toconduct safety and toxicology studies from scratchfor a new indication. Bioequivalence studies for theaddiction treatment indication had yet to be done,and the ideal dosing was unknown.85–87 Frank Vocci,a pharmacologist who had joined NIDA in 1989from the FDA, became Director of MDD in 1998.He would play a crucial role in the CRADA develop-ment, including in the face of disappointment withLAAM’s outcome.a

The time was propitious for Reckitts, as well.Disappointed with its analgesia business, the com-pany had contracted out buprenorphine commer-cialization to numerous companies worldwide andhad abandoned ethical drug development in theearly 1980s.63 John Lewis moved to Bristol Uni-versity, where Reckitts funded some pharmacologyresearch. The company’s reluctance to enter the ad-diction therapeutics arena reflected a more gen-eral attitude among pharmaceutical companies thatanalgesics might, as Bigelow put it, be “tainted” inthe eyes of prescribers and pain patients if also usedfor addiction.72 Methadone, for instance, had foundlittle use as a pain medication. As Chris Chapleo,now Reckitt & Benkhiser Director of BuprenorphineBusiness, recalled, Reckitts was under pressure atthat time because of “misuse, abuse, diversion ofbuprenorphine, the analgesic product” and its off-label use to treat addiction. An estimated half ofthe buprenorphine analgesic (Temgesic) supply inFrance was being used off-label to treat addicts.67

Diversion resulted in buprenorphine, an unsched-uled molecule, being put into the Psychotropic Con-vention in the late 1980s, with negative fall-outfor the buprenorphine market. Doctors hesitatedto prescribe scheduled drugs; sales of the buprenor-phine analgesic in France had dropped by 50% af-ter scheduling; patients had trouble obtaining it.67

The International Narcotics Control Board (INCB)was mounting pressure to move buprenorphinefrom the Psychotropic Convention to the more re-strictive Single Convention. Reckitts was also con-cerned by two “Phase 1–like” studies conducted

aSix European countries put LAAM on the market by1997, but it was withdrawn beginning in 2001, followingreports of severe cardiotoxicity associated with its use.88ci



by a Belgian psychiatrist, Marc Reisinger using apharmacy-prepared buprenorphine compoundfrom the analgesic. Though these supported Jasin-ski’s finding and showed that higher buprenorphinedosages were necessary for addiction treatment thanfor pain management, Reisinger’s studies involvedoff-label buprenorphine, which Reckitts felt it couldnot condone.67

Despite Reckitts’s ambivalence, the company wasfinally persuaded by Chapleo and O’Keeffe to“remove the For Sale sign and develop buprenor-phine for the treatment of opioid dependence”in partnership with NIDA, who “would be co-funding to ease the burden to Reckitts.”67 Reckittsbought back its U.S. distribution rights but hadto set up a U.S. company (Reckitts Colman Phar-maceuticals), as well as develop an infrastructure(secure warehouse services, import permits, etc.)before entering into the CRADA. The agreementwas finally ratified in 1994. According to Reckitts’snegotiators, the company was swayed by argu-ments about “social responsibility” toward drug ad-dicts85 and the ethics of withdrawing, buprenor-phine when patients were being treated with it forpain.67 The following year, in the wake of a con-taminated blood transfusion scandal and the AIDSepidemic among injecting drug users, France be-came the first country to approve buprenorphine(Subutex) for treatment of opiate dependence ingeneral medical practice, proving the national vi-ability of implementing the drug89 and prevent-ing Reckitts licensee Schering–Plough from losingits license because of off-label use of Temgesic.France framed Subutex partly as harm reduction,90

as would some Asian countries in the followingdecades.67

In the United States, buprenorphine developmentfaced funding issues, scheduling, and potential reg-ulatory problems, as well as competition with themethadone community. Public contributions to de-velopment eventually included millions of dollars incontracts and grants. Reckitts obtained orphan drugstatus for Subutex and Suboxone (the two buprenor-phine medicaments for addiction treatment) in theCRADA,85 arguing the rarely used Cost Recoveryprinciple; that is, that the company risked not re-cuperating what it invested (buprenorphine is moreexpensive to manufacture than methadone).91 Theorphan drug designation freed the company fromcompetition with lower-priced generics for seven

years.b Once Suboxone and Subutex were launched,postmarketing surveillance by an independent con-tractor was subsidized by Reckitts as a requirementof the approval for marketing.92,c

Most NIDA-funneled resources contributed tothe numerous clinical pharmacology studies be-tween 1980 and 1985, which compared variousroutes of administration and dosages, withdrawal,and cross-tolerance. Later studies concerned induc-tion, abrupt withdrawal, and short-term detoxifi-cation. In the 1990s, studies were extended to in-clude dose omission schedules, pharmacokinetics,and buprenorphine for pregnant, opiate-addictedwomen. These laid the groundwork for arguing thatbuprenorphine was not merely a “substitute ther-apy,” in order to differentiate it from methadone.

Buprenorphine proponents, however, perceivedmethadone regulation as an obstacle to pharmaceu-tical innovation for addiction treatment, an opinionthe IOM 1992 Report also held.84 As the moleculeproved less toxic than methadone or LAAM wheningested by nontolerant individuals, buprenorphinetreatment was thought to require less oversight. Andto compete with methadone, buprenorphine wasmainstreamed into medicine,67,85 which requiredamending the CSA requirement so physicians couldtreat patients with a Schedule V narcotic. France hadnormalized addiction treatment by allowing generalpractitioners to prescribe Subutex, as they would

bOriginally, Reckitts argued for orphan status on theprevalence principle that the drug would affect a rare pop-ulation. The FDA rejected Reckitt’s prevalence estimate,which was based on the number of treatment-seeking ad-dicts, and not on the estimated number of addicts (treatedand untreated) in the U.S. According to O’Keeffe, Subutexand Suboxone were the first drugs ever designated orphanstatus on an economic basis.85 The economic principleargument enabled Reckitts to obtain exclusivity for sevenyears, versus the 10 or 15 years they would have had under“normal” orphan drug status, making it one of the onlyorphan drugs based on this principle.cThe study, which included 18,596 interviews with ap-plicants to substance abuse treatment programs, 8,194surveys of federally certified physicians, as well as pub-licly available indicators of use and misuse of buprenor-phine and buprenorphine with naloxone shows a steadyincrease in diversion and abuse from 2005 to 2009, al-though at lower levels than methadone. Like studies inother countries, the authors suggested much diversionwas for therapeutic reasons.



any other treatment, in office-based practice.89 Ad-dicts in many countries appropriated Subutex as“a medicine for them.” 67 But NIDA, being a publicagency, could only provide the data used for schedul-ing and testify regarding proposed laws; it fell toReckitts and the network of pro-buprenorphine re-searchers and consultants to lobby for these changes.Lewis, for example, spent much time in Geneva con-vincing WHO to keep buprenorphine out of theSingle Convention and on a moderate schedule inthe Psychotropic Convention, as the outcome of thisdecision would affect the DEA’s view.

In the United States, Reckitts took the legislativeroute, with O’Keeffe as architect of a policy withcomplex technical and political repercussions, in-volving delicate negotiations with the FDA, DEA,SAMHSA, NIDA, Clinton administration, profes-sional groups, and politicians. The Drug AddictionTreatment Act (DATA) was finally passed in 2000.It allowed office-based physicians who completean 8-hour certification course to obtain a federalwaiver and treat opiate-dependent persons. PublicLaw 109–460 (2006) extended the patient cap from30 to 100 for physicians with at least one year’s clin-ical experience with buprenorphine. Subutex (foropiate-dependent pregnant women and lactatingwomen) and Suboxone received FDA approval in2002, but the DEA, which had expressed seriousreservations before DATA 2000 passed, rescheduledthem from Category 5 to Category 3.86

When DATA 2000 passed, the analgesic sectionat Reckitts (by then merged as Reckitt–Benkhiser)consisted of two people: O’Keeffe and Chapleo. In2002, Johnson was brought in. Since that time, theU.S. company has grown more than a hundredfoldprimarily due to the promotion of buprenorphine.Reckitts explicitly sought to move addiction fromcriminalization and toward medicalization throughits concept of the “treatment space.” Reckitts’ inter-national markets had previously focused on house-hold products and nonethical drugs, mostly in theCommonwealth). Whereas in 1997, Reckitts hadsigned a 15-year Global Agreement giving exclu-sive worldwide distribution rights for buprenor-phine hydrochloride prescription products, includ-ing Subutex and analgesics, to Schering Plough,67

essentially keeping buprenorphine’s growth at a dis-tance, in the early 21st century. Reckitts remodeledits “treatment space” vision as a global one. By 2010,it had bought back much of its sales and marketing

rights for Suboxone, Subutex, and Temgesic93,94 andassumed marketing in more than 30 countries inEurope as well as the United States, Australia, NewZealand, and South Africa and negotiated with othercountries to buy back distribution rights before theyexpired. Reckitts moved toward being “a wholly-owned international franchise for Suboxone andSubutex.”92 While treatment contexts are shapedby national and regional policy, as buprenorphinecirculates globally, it carries Western definitions of“addiction,” especially as an appropriate treatmentobject for medicine, though not without encounter-ing resistance in countries where addiction is heavilycriminalized.

In the United States, Suboxone lost the ex-clusivity afforded by its orphan drug status inOctober 2009. A year later, Reckitt–Benckiser Phar-maceuticals introduced Suboxone formulated as asublingual film, a patent-protected and “patient-preferred delivery system,”. . . “to address the po-tential loss of up to 80% of the revenues and prof-its of the Suboxone tablet business in the yearfollowing the launch of prospective generic com-petitors.”95 The company’s overwhelming finan-cial success can be attributed to Suboxone, whichaccounted for 23% of U.S. revenues for Reckitt–Benckiser in 2010.95

Historical tensions between maintenance andabstinence, medicalization and criminalization,and the complex interplay among patient choice,provider authority, and regulatory constraintsstructure the addiction therapeutics arena. Aimed asboth a social and a pharmacological “fix,” buprenor-phine must work at both levels if it is to workat all—that is, if buprenorphine is to shed thestigma of methadone symbolically. Buprenorphinefor opiate dependence emerged from the long questfor a pharmacotherapy that worked not simplyto block opiate effects but to attenuate them inways acceptable to addicted people. First exploredas a potential pharmacotherapy at the U.S. Pub-lic Health Service Hospital in Lexington obtainedthe status of an FDA-approved opioid addictiontreatment in the 1970s, and Subutex and Subxonewere launched in the United States almost threedecades later. The difficulties of coordinating pub-lic and private interests, local and global effects,changes in domestic regulatory mechanisms, andperceptions of addiction and its treatment chartedbuprenorphine’s tortuous, 30-year path to FDA



approval and market. Buprenorphine arose as amaintenance therapy at a time when addicts—likeother citizens—were expected to take personal re-sponsibility for health and healthcare, and wheresuch decisions were seen as individual matters ofchoice and political entitlement. Reckitt’s new treat-ment space dovetailed with this larger movementof decriminalization, destigmatization, and normal-ization of addiction treatment, and buprenorphinefinally proved to be the “holy grail”—an office-basedpharmacotherapy for opioid addiction.

Acknowledgments

We obtained much of the basis for this paperon May 18–19, 2009 at a workshop on the “His-tory of Buprenorphine” sponsored by the Univer-sity of Michigan Substance Abuse Research Center.We would like to thank John Traynor, director ofUMSARC, and James H. Woods for hosting thisevent. Participants included John Lewis, AndrewCowan, C. Robert Schuster, Don Jasinski, Chris-Ellyn Johanson, R. Ed. Johnson, Frank Vocci, andCharles O’Keeffe. A.L. would like to thank IsabelleFeroni for more than a decade of exchanges andcollaboration about buprenorphine. Some of theresearch on which this paper is based was madepossible through a grant from the MILDT-CNRS toINSERM U 379.

Conflicts of interest

The authors declare no conflicts of interest.

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