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 Sante´ et de la Recherche Medicale,´ UniversiteParisRen´ 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. [email protected]

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

pacity, the U.S. industrial and academic pharmacol- The early 20th century project to develop ogy was so underdeveloped that Harvard University nonaddicting analgesics pharmacologist Reid Hunt urged the chair of the Addiction therapeutics arose within the historical Division of Medical Sciences (DMS) of the National context of efforts to develop a nonaddicting anal- Academies of Science (NAS), National Research gesic that began in the United States in the early Council (NRC) to strengthen drug discovery, “the 1920s. Early 20th century efforts to respond to the field of medical research in which the United States is “opium problem,” through regulation and control most conspicuously backward.”3 This rationale later at the source of supply and to address public health led the NRC to adopt a committee formed to coor- concerns through innovation in the research lab- dinate efforts to identify “non-habit forming opiates oratory set the stage for the gradual shift in re- and local anesthetics so that the use of opium and searchers’ interests toward developing a treatment cocaine (the abuse of which almost balances the ben- for addiction therapeutics. Diplomacy directed to- efits) may be restricted or abolished.”3 Convened in ward control of opium and its derivatives drove 1921 by the New York City Bureau of Social Hygiene, the earliest interactions between the United States the Committee on Drug Addiction (CDA) under- and the League of Nations. Policy elites considered took the search for morphine substitutes as a way the opium problem to be an acute threat to na- to attack the root of the “opium problem,” which it tional public health that could only be met through considered to be not “vicious” (nonmedical) con- international collaboration on drug control policy sumption but medical use leading to addiction. The (p. 52 in Ref. 1).1,2 Pharmaceutical industry influ- CDA published The Opium Problem (1928), a hefty ence was typically represented by national govern- compendium reviewing 4,000 studies, which found ments at the time. Lacking in-house research ca- that while the “consensus of opinion of the authors

doi: 10.1111/j.1749-6632.2011.06352.x 124 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 chronic 1947, reported that “since no one drug can func- opium intoxication lies in the therapeutic use of the tion for all of these uses, it is necessary to replace drug,” there was rising heroin use for “purposes of the legitimate uses of morphine with a number of dissipation” (p. 13).4 Committee sponsorship was substitutes...[Ifitis...]possibletosubstitute assumed by the Rockefeller Foundation from 1932 for all legitimate uses of morphine other chemical to 1939, after which the CDA became part of the compounds without addiction properties, it should NAS/NRC and was relatively self-sustaining through render morphine an unnecessary commodity in in- modest contributions from the pharmaceutical in- ternational commerce” (p. 11).9 White noted that dustry and National Institute of Health (NIH; in “setting up a machinery for a specific purpose; that 1949 renamed National Institutes of Health). The is,ofanattemptatasolutionofadefiniteproblem Committee undertook chemical dissection of the of international importance” was new for the NRC morphine molecule, seeking to dissociate analge- Divison of Medical Sciences. The Committee was sia from addiction liability and emphasizing direct charged with reducing legitimate use by decreasing manipulation of the morphine molecule to develop physician’s prescriptions and proprietary remedies nonaddictive substitutes for each known medical containing narcotics, replacing each use of habit- use of morphine. forming drugs with a substance that was not habit- The solution to the “opium problem” was first forming but capable of producing the medicinal sought at the laboratory bench at a time when the action required, and reducing to a minimum the United States was becoming a major player within legitimate production of alkaloids and thus less- the evolving international drug control framework. ening the necessity for controls.10 The Committee For such a narrowly tailored goal to be understood was also asked to conduct public education semi- as meeting a broad social problem of unclear etiol- nars on the indispensable uses of morphine, to seek ogy, it had to be translated into a fundable research to prepare by synthesis and analysis compounds program. Reliable methods to test compounds in without addiction fractions, and to study the ef- animals and human beings had to be developed fects of these compounds in animals and later in and validated. In the CDA’s first decade, some human therapy. White arranged with Morris Fish- 150 compounds were produced and evaluated; all bein, editor of the Journal of the American Med- but one—Metopon (5-methylhydromorphone)— ical Association, to publish the Committee’s rules demonstrated the elusiveness of the goal.5 and regulations governing morphine prescription, Although iatrogenic addiction had declined with which was released as The Indispensable Uses of changes in medical practice,6 physicians remained Narcotics.11 the chief vectors of opiate addiction in the early The Committee’s research program was a highly 20th century. The Committee’s goals dovetailed organized, centrally orchestrated effort—one of the with an American Medical Association (AMA) re- first scientific collaborations that focused the U.S. form agenda to “reduce indications for opiates to government scientific resources on solving a social an irreducible minimum” (p. 95).7 CDA leader- problem. Cooperation between CDA and the U.S. ship supported scientific investigation of narcotics, Public Health Service (PHS) was secured by strate- including analyses of the chemical and biological gic appointments. Clinical studies commenced in literature on addiction alkaloids; formulation of 1933 at the federal penitentiary in Fort Leaven- rules and regulations for legitimate use of alkaloids worth, Kansas. However, in 1929 the U.S. Congress having addiction properties, and education of physi- passed the Porter Bill, authorizing construction of cians and the public about these rules; and “replace- “narcotic farms” to rehabilitate addicts. When the ment of all present use of addiction alkaloids by first U.S. Narcotic Farm opened in Lexington, Ken- substitutes having no addiction properties” (p. 11) tucky, in 1935, a tiny research laboratory was housed (emphasis ours).8 within the 1,500-bed institution. In May 1938, the Morphine was the Committee’s target because PHS broadened the NIH role in the Committee by it had numerous specific uses in clinical prac- establishing a chemotherapy unit consisting of sev- tice, many of which, according to the first com- eral chemists who had been associated with CDA, mittee report, could already be satisfied by other including Nathan B. Eddy, Erich Mosettig, Everett drugs. William C. White, CDA chair from 1929 to L. 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, Clifton Section of the World Health Organization (WHO); K. Himmelsbach, who had worked with Eddy Maurice H. Seevers, whose University of Michigan to pioneer the “morphine substitution technique” laboratory the committee had designated for animal developed to compare the addiction liability of novel testing; Eddy and Small from NIH; and representa- compounds to morphine. The Himmelsbach tech- tives of the Armed Services, FDA, AMA Therapeutic nique was based on the principle that, “A substance Trials Committee, and the American Drug Man- which will support and maintain the ‘addicted state’ ufacturer’s Association. Amidon (methadone) was is essentially addictive in and of itself” (p. 26).12 one of the postwar committee’s first considerations, Research objectives included “new treatment and as several pharmaceutical firms were interested in substitution techniques, intensive study of physico- manufacturing methadone or derivatives. Nathan chemical, psychiatric, and psychological changes re- B. Eddy, who had worked with the committee since sulting from single therapeutic and repeated doses 1930, proposed that CDAN serve as a clearinghouse of morphine in the non-tolerant individual, dur- to which manufacturers of analgesic drugs submit ing stabilized addiction, and in the post-addiction information useful for committee review of addic- state” (p. 30).12 Himmelsbach investigated the rela- tion liability and extent of clinical usefulness. tionship of chemical structure to addictiveness,13–15 By the late 1940s, the U.S. government was ac- creating a point-score system to track the “Mor- tively attempting to determine the national and in- phine Abstinence Syndrome.”16 Based on close ob- ternational controls to which new synthetic drugs servation of 65 subjects passing through cycles would be subjected. At the first postwar CDAN of tolerance, addiction, and withdrawal or “absti- meeting, Anslinger gained the Committee’s ap- nence,” Himmelsbach generated hourly and daily proval of a draft protocol to bring synthetic drugs point scores that yielded a method for calculating under international control. Whereas the opium- the intensity of abstinence and predicting its course. producing countries of the developing world viewed He had previously gained insight into techniques the new synthetics as dangerous and difficult to con- for quantitatively comparing degrees of “addictive- trol, the United States feared it could not stem the ness” through study of desomorphine and meto- flow of opiates from producing countries.1 CDAN pon, a drug developed by Small and marketed for provided recommendations concerning levels of chronic pain until the early 1950s. Metopon was control and indications for a drug’s use at the in- considered proof of concept for the idea upon which ternational level. The UN mandated the WHO Ex- the Committee was configured—the dissociation pert Committee on Drug Dependence (formerly of analgesic activity from the undesirable tendency “on Habit-Forming Drugs” and later renamed “on to produce dependence and respiratory depression. Drugs Liable to Produce Addiction”) to recommend Simultaneously, German chemists produced pethi- levels of control to regulatory bodies. Along with the dine (also called meperidine and trade-named De- WHO section that it advised, the Expert Commit- merol), which was modified during World War II tee rapidly forged a principle of balancing medical to produce methadone, the synthetic analgesic re- utility against the social risks of abuse. The inter- covered by the Allies during a U.S. Department of national treaties, the Single Convention of 1961, Commerce investigation of German wartime indus- and Psychotropic Convention of 1971 reflected the tries.17 During the war, the Committee’s operations view that the more medically useful a drug, the less were suspended, but methadone came to the Com- strict the controls should be.19 In pharmacology, mittee’s attention just as it resumed operation after Eddy et al. demonstrated that synthetic drugs with the war’s end (p. 52).18 “morphine-like effects are as good and as bad, as a Renamed the Committee on Drug Addiction and class, as the drugs of natural origin.”20 Eddy played Narcotics (CDAN), the Committee’s first postwar a leadership role in the Expert Committee from its meeting was held at the NRC in 1947. Attending founding until his death. CDAN members served on were Isaac Starr, the newly appointed chair; Harry J. it and supplied data to it, shaping its drug definitions Anslinger, chief of the Federal Bureau of Narcotics and criteria for control. The Expert Committee, for (FBN); Raymond N. Bieter, Head of Pharmacology example, depended “in large measure upon receipt at University of Minnesota Medical School; Dale of information” from American research, funneled C. Cameron, later chief of the Drug Dependence through CDAN (p. 11).18

126 Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c 2012 New York Academy of Sciences. Campbell & Lovell History and development of buprenorphine

The Addiction Research Center (ARC), as the lab- who joined the group in 1957. Martin studied the oratory at Lexington was called after 1948 when underlying neural mechanisms of addiction, and it joined the newly formed National Institute of had immersed himself in Himmelsbach’s early find- Mental Health (NIMH), studied methadone in ings, becoming convinced that tolerance was an ex- human subjects, finding that it produced a milder, tremely complex neuronal phenomenon. He set out more prolonged version of the abstinence syndrome to understand the “neuronal events that are respon- than other opiates, according to the Himmelsbach sible for morphine’s action as well as for a develop- scale. Research Director Harris Isbell, who had re- ment of physical dependence and the emergence of placed Himmelsbach, instituted methadone detox- the phenomena of early and protracted abstinence” ification at Lexington after 1948 for clinical man- (p. 108).24 Martin, a physician and World War II agement of opiate withdrawal. Isbell later opposed Army veteran, had prepared a doctorate in neu- using methadone for maintenance given the re- ropharmacology under Klaus R. Unna, who, while sults of studies he and Abraham Wikler conducted working for Merck, discovered that nalorphine, a on former morphine and/or heroin addicts in the narcotic antagonist, could “prevent or abolish the late 1940s indicating that the subjects expressed action of morphine.”25 Martin worked in a highly increased satisfaction as dosage increased.21 They original and theoretical way with a close-knit circle concluded that “narcotic drug addicts would abuse of chemists innovating in the analgesic area, includ- methadone and would become habituated to it if it ing Sydney Archer, Louis Harris, Andrew Keats, and were freely available and not controlled” (p. 892).21 Everett May, from Small’s group.26 Highly active in They also noted that methadone “completely alle- the Committee, this network expanded in the late viated the morphine abstinence syndrome in man” 1960s to include U.K. chemist John Lewis, whose and itself exhibited a mild abstinence syndrome. work would become crucial to bringing buprenor- On the basis of their findings of “satisfactory sub- phine to the attention of the ARC group. jective reaction” to methadone, they argued that Through its historical role in relation to the methadone would present a potentially serious pub- CDAN (which became the Committee on Prob- lic health problem if manufacture and distribution lems of Drug Dependence [CPDD] in 1965), ARC were not controlled.22 researchers enjoyed constant access to new anal- Despite controls, methadone was used as an gesic compounds. During the 1950s and 1960s, “office-based” addiction treatment by a handful the Committee turned to studying the narcotic an- of physicians who prescribed it in the 1950s; the tagonists, including nalorphine;27–32 naltrexone;33 New York State Department of Mental Health ran LAAM (long-acting methadyl acetate), a long- an informal methadone maintenance program in acting derivative of methadone May synthesized un- 1959.23 However, the rabidly antimaintenance Fed- der CPDD auspices;34 cyclazocine;35 phenazocine;36 eral Bureau of Narcotics (FBN) harassed physi- and pentazocine.37 Although dating from Commit- cians who prescribed methadone or other opiates. tee discussions in the 1940s, this route of experimen- Neither Anslinger nor CDAN researchers consid- tation intensified during the synthetic flood of the ered maintenance a viable solution to the prob- 1950s. At the January 1953 CDAN meeting, Isbell lem of “unsafe analgesics,” as it was framed. By the had urged Henry K. Beecher and Louis Lasagna to 1950s, the Committee’s drug development hopes run clinical trials of a nalorphine–morphine com- fastened upon another class of drugs—the narcotic bination in order to establish nalorphine’s analgesic antagonists—as an alternative to agonists like mor- efficacy for post-operative pain. While these drugs phine and methadone. A spirit of experimentality were then being primarily studied as analgesics,38 permeated the organizations and research networks suggestions surfaced at Lexington that narcotic an- through which addiction researchers and clinicians tagonists might help prevent relapse. Another path- then worked. way pursued from 1952 onward was May’s work building upon incomplete morphine molecules, The mid-20th century project to develop which led to the production of phenylmorphans narcotic antagonists as “safe analgesics” and benzomorphans (p. 676 in Ref. 40).39,40 By In 1963, Isbell and Wikler retired, handing over the the mid-1960s, the Committee’s efforts to find a ARC to neuropharmacologist William R. Martin, “chemopharmacological approach to the addiction

Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c 2012 New York Academy of Sciences. 127 History and development of buprenorphine Campbell & Lovell problem” were focused on the narcotic antago- new analgesics with potential to produce depen- nists.40 dence from going onto the market. More than 30 years into its quest, the Committee By the mid-1960s, the goals of the Committee was not overly optimistic about the chemophar- (hereafter referred to as CPDD), underwent a con- macological approach. Aware that heroin addic- ceptual shift toward finding a pharmacotherapy for tion could not be regarded solely as iatrogenic, addiction treatment and relapse prevention as a re- the Committee did not think that a new medicine sult of Martin’s experimental work with the nar- could effectively treat nonmedical addiction; rather, cotic antagonists, which he felt were the best can- it focused on preventing potent new addictive didate drugs for analgesics that did not produce compounds from being marketed. CDAN’s rele- dependence and for addiction therapeutics. Martin vant historical touchstone was the “heroin mistake” first studied cyclazocine, a long-acting, orally ef- stemming from initial claims that heroin was a fective narcotic antagonist developed at Sterling- “nonaddictive” alternative to morphine for analge- Winthrop, as a “modality for preventing recidivism sia (p. 673).40 The “solution” to the heroin prob- in ex-heroin addicts.”35 Martin set up a trial based lem had been framed as an alternative analgesic on Wikler’s postulation that “conditioning”—the that would displace the need for opium production. association of positive pharmacological effects and Without the need for morphine or codeine (work alleviation of withdrawal distress with specific envi- was underway to replace codeine as an antitus- ronmental “cues” and social settings—played a role sive), the global opium supply could be controlled. in perpetuating addiction.42 Wikler reasoned that However, by the 1960s, the Committee under- it might be possible to “extinguish” associations by stood that its “chemical-pharmacological-clinical allowing addicts to inject an antagonist drug that program” was founded upon an erroneous hy- would block the effect of the agonist drug. This hy- pothesis concerning the potential ease of dissoci- pothesis dovetailed with Martin’s observations that ating the analgesic effects of morphine from the cyclazocine produced a different type of physical de- dependence-producing and respiratory-depressing pendence than morphine.35 In suggesting that cy- effects (p. 674).40 The Committee turned toward clazocine might be efficacious as a new method for narcotic antagonists upon the suggestion of Andrew treating opiate addiction, Martin built upon find- Keats, hoping that this class of drugs would be clin- ings that nalorphine, a narcotic antagonist his men- ically useful as analgesics.41 tor (Unna) had developed at Merck, competed with Recognizing that if even one of the new antago- morphine at a receptor site but worked through a nists proved a sufficiently powerful analgesic with- different mode of action. To make sense of this ob- out undue side effects, Eddy noted that it would servation, Martin introduced several concepts for still not “solve the addiction problem overnight which he became known: multiple opiate receptors’ (p. 679).40 Social and economic factors, he indi- “competitive antagonism” at the receptor level, and cated, were paramount: “We shall still have the “receptor dualism.”43–45 Another piece of the puzzle opium-producing countries. ...We shall still have had to do with why the effects of abstinence should the established machinery for illicit production and be so long lasting. Martin’s experiments conducted distributionofheroin...[and]weshallstillhave with Donald Jasinski, who joined the ARC in 1965 the social and psychological forces that encourage from a postdoctoral position with Unna, led them to potential addicts to dose themselves with drugs” (p. postulate a “secondary” or “protracted” abstinence 679).40 Eddy heralded the narcotic antagonists as syndrome that differed from the “explosive, early progress in managing, rather than resolving, addic- abstinence syndrome” tracked by Himmelsbach tion problems: “We thought there might be found (p. 2).46 Tracing protracted abstinence, Martin and among the opiate antagonists one with the com- Jasinski found that its characteristics varied among bination of antagonistic and analgesic properties individuals but fell within the range of normal phys- which would give adequate clinical analgesia with- iological variables and were difficult to discern un- out excessive and disturbing side effects” (p. 679).40 less researchers were in close proximity with sub- CDAN was not naive to nonmedical use but rather jects. Martin and Jewell W. Sloan observed negative conceived of its role as acting within the national attitudes in subjects in an 18-month study of pro- and international drug control apparatus to prevent tracted abstinence and discussed their possible role

128 Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c 2012 New York Academy of Sciences. Campbell & Lovell History and development of buprenorphine in relapse, with a rationale for using narcotic antag- was occurring among the U.S. addiction research onists in treatment of ambulatory narcotic addicts: network. “the view has been presented that the chronic ad- From safe analgesics ministration of narcotic antagonists would prevent to “chemotherapeutics” the exacerbation of protracted abstinence and may provide a circumstance whereby conditioned absti- In 1964, Vincent Dole and Marie Nyswander ini- nence and conditioned drug-seeking behavior could tiated a pilot research program on methadone be extinguished.”47 While it was optimistic that fur- maintenance at the Rockefeller Institute (later re- ther developments in neuroscience would yield a named the Rockefeller University).49 They cast specific pharmacotherapy for addiction treatment methadone as a medication that had the social effect and relapse prevention, Martin’s studies contained of “block[ing] the normal reactions of addicts to the germ of a shift in the addiction research com- heroin and permit[ting] them to live as normal cit- munity toward addiction therapeutics. izens in the community” (p. 304). 50 In 1966, Dole Relapse prevention had long been a problem for reported on the first 84 methadone maintenance clinicians treating drug addicts. The idea that a phar- patients to the Committee, which concluded that a macotherapy could support relapse prevention by “significant number of patients through methadone keeping patients in treatment helped change the goal maintenance management have attained a reason- from a nonaddictive analgesic to addiction thera- able degree of social rehabilitation. Their depen- peutics. CPDD held that the “ability of an antagonist dence has not been ameliorated, it has not been to suppress the satisfying response (euphoric effect) treated, it may have been augmented, but the patient of an opiate (heroin)” could deter relapse; even more and society have gained” (p. 114).18 The Commit- useful would be “prolongation of antagonistic ac- tee’s lukewarm reception of the methadone main- tion, either in an inherently longer-acting antagonist tenance pilot program and grudging acceptance of or a depot preparation” (p. 24).18 The Committee its social benefits was no surprise. The Commit- regarded an “antagonist-suppressant” as superior to tee had never favored agonist maintenance. Debates agonist maintenance. In 1970, the Committee em- over morphine maintenance had occurred in the barked on an intensive search for a drug exhibiting 1920s as part of the context in which the Com- prolonged antagonistic action. Naltrexone had been mittee was formed. In the 1950s, there was an ac- synthesized in 1963 at Endo Laboratories, a small tive national debate over the practice of morphine pharmaceutical company with whom Martin con- and/or heroin maintenance conducted conjointly sulted to develop the drug before DuPont purchased by the American Bar Association and the Ameri- the company and dropped the project. Naltrexone can Medical Association. At that time, the Com- was conceptualized as a “blockade” that fended off mittee had opposed maintenance, aligning with the agonist access to receptor sites. While naltrexone FBN against it. In the 1960s, the FBN was com- would be approved as a pharmacologic adjunct to bined with the Bureau of Drug Abuse Control, an treatment for opioid addiction and alcohol in 1984, agency within the Department of Health, Educa- it never gained social acceptability among physi- tion and Welfare, to form the Bureau of Narcotics cians or addicted patients despite appearing to be a and Dangerous Drugs (BNDD) in 1968, which pharmacologically perfect solution at the receptor in 1973 became the Drug Enforcement Adminis- level.48 Naltrexone was later touted as an anticrav- tration (DEA). Committed to safeguarding public ing medication that had a “healing” effect on the health against “unsafe analgesics,” the Committee endorphin system. CPDD also considered a novel aligned with the drug control apparatus in viewing combination in which oral opiates would be for- methadone maintenance with skepticism. Similarly, mulated with a small amount of naloxone to pre- the WHO Expert Committee on Drug Dependence vent diversion of morphine-like analgesics. In the considered methadone maintenance a research ap- mid-1970s, a search for the optimal components proach but not an established treatment (p. 112).18 of such possible agonist–antagonist combinations Dole and Nyswander characterized such attitudes as commenced. By the early 1970s, however, the social those of a stodgy addiction research establishment and political context had changed in ways that facil- opposed to methadone maintenance on political itated the shift toward addiction therapeutics that grounds.51

Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c 2012 New York Academy of Sciences. 129 History and development of buprenorphine Campbell & Lovell

New entrants to the field exemplified the attitude redistribution of the drug into illicit channels” of experimentality then pervading drug treatment. (p. 114)18 Limiting diversion dominated discussions Many embraced methadone maintenance despite of methadone within the domestic drug control ap- acknowledging its limitations. For instance, Jerome paratus in the early 1970s. H. Jaffe, who had spent a year working on the clini- Despite the widespread support for methadone cal side of the U.S. Narcotic Farm in the early 1960s, maintenance, there remained recognition of its lim- had heard Martin’s 1964 paper to the Committee itations within the addiction research community. on cyclazocine and theorized that narcotic antag- Research on alternative medications ranging from onists might work to prevent relapse, keep addicts long-acting methadone to narcotic antagonists con- in treatment, and reduce overdose events.52 In New tinued even as methadone maintenance expanded. York City, Jaffe and Leon Brill detoxed former heroin Research on long-acting methadone (LAAM) had addicts unable to access methadone maintenance been sponsored by the NIMH Division of Nar- and put them on cyclazocine obtained from Sterling cotic Addiction and Drug Abuse (DNADA) in the Winthrop. Although he ultimately switched patients late 1960s.56 Understood to lack abuse liability, to oral methadone due to ease of use compared to LAAM and the narcotic antagonists were thought short-acting injectables, Jaffe considered the nar- less likely candidates for diversion. Methadone treat- cotic antagonists as having therapeutic potential ment centers, with the notable exception of Dole and for optimizing compliance and extending treatment Nyswander’s program, operated under relatively in- duration.53 Jaffe spent six months with Dole and formal FDA-issued Investigational New Drug (IND) Nyswander learning the ropes of methadone main- designations, until SAODAP and FDA jointly im- tenancebeforehemovedtoChicagotostartamulti- posed formal regulations to create a “hybrid IND- modality drug treatment program, the Illinois Drug NDA (New Drug Application) that acknowledged Abuse Program, which brought his work to the at- the safety and efficacy of methadone maintenance tention of the Nixon administration. as a treatment but imposed a number of conditions The Nixon administration turned to methadone on how it could be used,” in 1973 (p. S5),57 resulting maintenance as a method for crime control and as in a system of stand-alone clinics and restriction of a way to respond to concerns that a high percentage methadone in private practice. In 1974, Congress of heroin-addicted Vietnam veterans were returning became concerned with methadone diversion and opiate-addicted.54,55 In 1971, Nixon created the Spe- amended the Controlled Substances Act (CSA), in cial Action Office for Drug Abuse Prevention (SAO- 1970. to give DEA considerable powers despite the DAP) and appointed Jaffe director. Despite concerns inception of the National Institute on Drug Abuse about methadone’s limitations, including the fre- (NIDA) and sunset of SAODAP in 1973. Many clin- quency of dosing, refusal, and refractory cases, Jaffe icians, including Dole and Jaffe, came to view the played a crucial role in expanding methadone main- methadone regulations as government interference tenance as a treatment modality in the United States. with the practice of medicine.52 The restrictive cli- The Committee also shifted toward support for mate had led SAODAP to prioritize development agonist maintenance in the 1970s and assisted of narcotic antagonists; The White House office in creating the first practice guidelines governing sought to contract with CPDD to conduct Phase methadone maintenance, “Narcotics and Medical III studies on narcotic antagonists.58 While both Practice,” which were issued in 1971 by a joint com- organizations agreed that it was desirable to move mittee composed of NAS/NRC committees, includ- beyond methadone maintenance in the addiction ing CPDD, and the AMA Council on Mental Health. therapeutics arena, the organizational complexities These guidelines stated that “methadone mainte- of arranging for CPDD to run a SAODAP-initiated nance is not feasible in the office practice of pri- Narcotic Antagonist Project delayed the process. vate physicians” because they could not meet all of Relapse was SAODAP’s target. Primary sources the therapeutic needs of such patients. Concerns indicate that the push to develop narcotic antag- about methadone diversion played a major part in onists as addiction treatment drugs was driven the decision not to allow office-based methadone by a search for a viable alternative to methadone prescription, as physicians in private practice were maintenance.58–59 Narcotic antagonists were sug- considered incapable of “assur[ing] control against gested as a “therapeutic maintenance agent for

130 Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c 2012 New York Academy of Sciences. Campbell & Lovell History and development of buprenorphine opiate-dependent individuals”59 on the assumption tion research, his rationale for continued investment that the high recidivism rate among opiate addicts was the compelling need to develop alternatives to resulted from a “biochemical abnormality induced methadone (agonist) maintenance. Still at the ARC by the prolonged use of a narcotic” or a continuing in Lexington, Jasinski turned his scientific attention “psychological dependence” that could be blocked to addiction therapeutics. Both researchers pointed by an antagonist long enough for the behavior to to buprenorphine as a sign of progress: “Recogniz- be “decondition[ed]” (p. 1).59 Long-acting antago- ing the possibility of partial agonists of the morphine nists were ruled out because of “considerable ago- type such as profadol, propiram and buprenorphine nist activity,” but a few series of new compounds and evolving methods for identifying them have were being shown to have strong antagonist prop- opened the possibility of a narcotic analgesic whose erties with little or no agonist activity (p. 2).59 Four agonistic activity will be great enough to fulfill clin- such compounds that appeared “very promising” ical expectation but not produce dangerous side ef- to SAODAP officials were almost through the ani- fects or a clinically significant degree of physical mal and human testing process for safety and toxi- dependence.”62 The fervor that developed among city. Although these compounds were ready to en- buprenorphine’s champions must be understood in ter large-scale, Phase III human trials, the National relation to the symbolic role the drug played in jus- Academy made it clear to SAODAP that it would not tifying continued federal investment in addiction allow CPDD to assume responsibility for drug de- research. velopment or clinical trials management despite the Building on SAODAP’s narcotic antagonist social and political climate surrounding methadone project, NIDA published a series of research mono- in the early to mid-1970s making narcotic antago- graphs on drug development in the mid-1970s.63–65 nists look comparatively hassle-free. The SAODAP One monograph named naltrexone as the most decision to develop narcotic antagonists was based promising of these “new” methods.65 The editors on their potential clinical value for treating patients introduced NIDA’s “newly established drug devel- unwilling or unable to participate in methadone opment program,” first applying the term “orphan maintenance, including “young users and early users drug” to addiction treatment: “With increasing fre- inappropriate as maintenance subjects.”59 Despite quency, Federal agencies are being called upon to the CPDD’s sustained interest in the development evaluate and develop new drugs and treatments for of antagonists for treatment of narcotics addiction, a wide variety of diseases and related conditions. NAS president Philip Handler declined to allow The so-called ‘orphan’ drugs, or drugs of little or CPDD to assume a managerial role in conducting limited commercial value, are being shunned by the clinical trials. Instead he created a new Committee pharmaceutical industry, due primarily to the ever- for the Evaluation of Narcotic Antagonists (CENA), increasing developmental costs and risks associated which conducted a study of naltrexone under NAS with new drugs. Thus, within the Public Health Ser- auspices.60 vice, a drug development effort has emerged to fill The National Academy of Sciences reorganized its this void.”65 Orphan drug designation would be- committee structure in 1975, leading to the termi- come key to buprenorphine’s career as an addiction nation of CPDD as an NRC committee. While the therapeutic. Committee had played a unique and invaluable role Buprenorphine’s career as an addiction during its long and productive existence, the emer- therapeutic gence of drug abuse as a national issue of major importance had attracted many new organizations Buprenorphine was discovered in 1966, at the re- with greater resources that overshadowed CPDD’s search labs of a home products company, Reckitt once unique capabilities.61 & Colman (hereafter Reckitts), in Hull, England. Other uncertainties also pervaded the addiction Working for the company was Oxford-trained research arena. The Federal Bureau of Prisons de- chemist John Lewis, a doctoral student of the Nobel cided in April 1976 to phase out all participation prizewinning organic chemist, Sir Robert Robinson, of federal prisoners in clinical trials and shut down who elucidated the active structure of morphine in the ARC’s prison recruitment channel. When Mar- 1925. Kenneth Bentley, father of the “Bentley com- tin traveled to Washington, DC, to defend addic- pounds,” was a postdoctoral researcher at Oxford

Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c 2012 New York Academy of Sciences. 131 History and development of buprenorphine Campbell & Lovell when Lewis did his graduate studies there. Bent- tential. According to Jasinski’s scheme, propiram ley went on to McFarlan Smith in Edinburgh, then and buprenorphine fit category 3.69 Interest shifted the main U.K. producers of opium alkaloids. In to these “partial agonists of the morphine type,” 1958, the company entered into joint venture with which did not constitute a homogenous class due Reckitts (1958–1963) to develop over-the-counter to their intrinsically different capacities for pro- analgesics. According to Lewis,66 Bentley laid the ducing euphoria, sedation, and psychotomimetic “chemical foundations” for the Reckitts opioid drug effects.70 development project in the 1950s. He believed At annual CPDD meetings from 1975 on, Jasinski that “opioids with structures substantially more suggested that buprenorphine usefully combined complex than morphine could selectively retain the the characteristics of methadone with those of a pure desirable actions whilst shedding the undesirable opiate antagonist and effectively blocked morphine side effects,” a vision convergent with that of Eddy (p. 5).71 Jasinski singled out buprenorphine as hav- and the Committee. In 1963, Reckitts took over the ing an “especially unique pharmacology in man” be- joint project, after McFarlan Smith was absorbed cause it produced “very little physical dependence” into another company.67 Reckitts developed two un- even with chronic administration (p. 290S).69 Citing successful opiates (etorpine, a potent ␮-agonist, and his 1978 study, he speculated that buprenorphine its antagonist),67 before putting buprenorphine into “would not only have a therapeutic application as Phase 1 studies on “committed volunteers” includ- an analgesic of low abuse potential but also as a ing Lewis himself,66 in the late 1960s. new type of drug treatment of narcotic addiction.”69 Reckitts supplied buprenorphine to the ARC re- Jasinski heralded buprenorphine’s unique potential searchers in Lexington throughout the 1970s, and because it alone produced long-lasting “changes in ARC’s Jasinski consulted regularly with the com- feelings that are acceptable to addicts,” and was pany.67 In 1972, Lewis disclosed buprenorphine’s “less toxic than methadone,”70 declaring that the pharmacological profile at the annual CPDD meet- committee’s 50-year project to “potentially utilize ing. While an immediate impact seems not to have narcotics therapeutically to both relieve pain and occurred, Lexington researchers went on to study treat addiction without the production of physi- buprenorphine as a potential addiction treatment cal dependence” had yielded buprenorphine, which drug because of its combination of analgesic (ago- “appears to have the advantage of both methadone nist) and antagonist properties. According to Lewis, and naltrexone but without the major disadvan- “The story of the development of buprenorphine as tage of each” (p. 85).70 For at least some parties, an addict treatment” [emphasis ours] began in 1975, the search had funneled down to one candidate when Jasinski countered growing opposition to us- drug. ing prisoners as clinical research subjects by arguing Given the enthusiasm for buprenorphine within that many prisoners were addicts and the pharma- the addiction research network, its meandering path cology of buprenorphine made it such an “attrac- to market as an addiction therapy is puzzling. Why tive candidate” as a treatment for opiate dependence did it take almost three decades after Martin and that its human abuse potential was in urgent need of Jasinski’s recognition of buprenorphine’s therapeu- study.66 Jasinski et al. announced the addiction ther- tic potential for it to be approved by the FDA for apeutics potential of buprenorphine in a landmark treatment of opioid dependence? Buprenorphine paper in 1978.68 faced many hurdles, including scheduling issues; In 1979, Jasinski classified the narcotic antago- reluctance of pharmaceutical companies to take nists into three groups: (1) compounds that pro- on addiction medicaments; fall-out from experi- duced agonistic effects that do not resemble mor- ment, diversion, and abuse of its analgesic form71; phine (nalorphine and cyclazocine), (2) compounds and still restrictive addiction treatment systems. As that do not produce agonistic effects (naloxone and with methadone maintenance, many within the ad- naltrexone), and (3) antagonists that produce ago- diction research enterprise had become convinced nistic effects that resemble those of morphine be- of buprenorphine’s uniqueness as an opioid ad- cause they are also partial agonists of morphine. diction treatment. However, the social and politi- By then, six category 1 narcotic antagonists had cal context was quite different, given the maturity been introduced as analgesics with low abuse po- of the drug regulatory apparatus, the changing

132 Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c 2012 New York Academy of Sciences. Campbell & Lovell History and development of buprenorphine knowledge base in the field, and what had several development studies of buprenorphine and been learned from the experience of methadone published results from the first pivotal clinical trial maintenance delivery through a stand-alone of buprenorphine in 1992.78 Following his retire- clinic system detached from office-based medical ment from the U.S. Public Health Service in 1991, practice. he joined the faculty of the BPRU at Johns Hopkins In 1979, following the ban on use of federal where he continued to conduct clinical trials with prisoners as research subjects, NIDA had moved buprenorphine funded by NIDA79–80 and dedicated the ARC’s Clinical Research Program, now under his scientific career to bringing buprenorphine to the direction of Jasinski, to the medical campus market as an addiction treatment. of The Johns Hopkins University (JHU) in Balti- Congress charged NIDA with assuming respon- more, Maryland; the preclinical program followed sibility for new addiction treatment methods in in 1981. The JHU site was chosen partly because the early 1980s. CPDD continued meeting annu- Baltimore provided a suitable source of research ally, although its drug development and evaluation subjects: inner-city heroin addicts.72–73 Addiction programs shrank. In February 1983, CPDD held a researchers considered it unethical and unwise to symposium on agonist-antagonists that included a carry out research involving addictive substances on review of buprenorphine presented by John Lewis. people who were not or had not been addicted. Fur- At this symposium, Martin attributed his recogni- thermore, residential laboratories were necessary. As tion of the possibility of developing a “less toxic, Martin told an interviewer in 1980, he “would never less addicting drug by developing a partial agonist conduct an experiment in which I chronically ad- of the morphine type” to the studies he had con- ministered a potentially addicting drug to a patient ducted with Jasinski on buprenorphine in the dog, who could leave the setting at will.”74 which laid the foundation for understanding that The Baltimore buprenorphine studies, conducted “these antagonists do things that morphine does not bytheJHUBehavioralPharmacologyResearchUnit do...[theyare]muchsaferdrugs...theirabuse (BPRU) headed by George Bigelow, grew out of the potentiality is less . . . they have a unique pharma- ARC’s move to the Hopkins campus, which brought cology that probably provides us hints about where buprenorphine to Baltimore. Bigelow recalled that we can go further in the future” (p. 84).81 Jasinski the ARC brought with them “connections to new spoke to buprenorphine’s advantages over naltrex- drugs, the pharmaceutical industry, and the med- one, noting that his subjects liked buprenorphine ications development field, in a way that we had better, and “felt comfortable on it. The induction not really had before. In particular, they brought ac- of a feeling state that they found salient following cess to buprenorphine, which was difficult to make buprenorphine was certainly there. . . Most of our and supplied only by Reckitts. Don Jasinski had been subjects told us that it was, in fact, the most reinforc- working with buprenorphine and had published the ing drug that they had ever used” (p. 95).81 Despite first paper suggesting it could be useful in addiction this caution, buprenorphine was offered as a “safe treatment.”75 The BPRU collaborated early on with and effective mode of pharmacotherapy for heroin ARC researchers, including on a study evaluating addiction.”81–82 buprenorphine in comparison to methadone76 and By 1985, injectable buprenorphine had been another evaluating a range of doses of buprenor- marketed for analgesic applications in 29 coun- phine in an opioid challenge.77 Bigelow recalled tries and the sublingual tablet in 16 countries. In that these “mark[ed] the primary beginnings of the United Kingdom, Reckitts had launched in- using that methodology and incorporating [ARC] jectable buprenorphine for severe pain in 1978, with methods in our studies.”75 One pharmacologist, the sublingual analgesic following in 1982. It li- R. Ed Johnson, who had compounded buprenor- censed Norwich–Eaton to distribute buprenorphine phine for Martin and Jasinski’s studies while a phar- hydrochloride (Buprenex) in the United States, macist in Lexington, assisted Jasinski in moving the where the analgesic was launched in 1985, after ARC’s Clinical Research Program from Lexington FDA approval. However, scheduling incited lengthy to Baltimore in 1979. While working at the ARC struggles. Scheduling was still (and remains) an (renamed the NIDA Intramural Research Program artifact of almost a century of domestic drug in the 1990s), Johnson served as lead investigator on policy culminating in the 1970 U.S. Controlled

Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c 2012 New York Academy of Sciences. 133 History and development of buprenorphine Campbell & Lovell

Substances Act (CSA) and, internationally, the Sin- diversion). Reckitts was NIDA’s obvious choice for a gle Convention of 1961 and Psychotropic Con- Cooperative Research and Development Agreement vention of 1971. Domestic and international con- (CRADA), as another company would have had to ventions are based on proving pharmacological conduct safety and toxicology studies from scratch equivalence. The classical antagonists, such as for a new indication. Bioequivalence studies for the naloxone, naltrexone, and nalorphine, catalyzed addiction treatment indication had yet to be done, considerable arguments about whether they re- and the ideal dosing was unknown.85–87 Frank Vocci, ally fit the definition of dependence-producing a pharmacologist who had joined NIDA in 1989 drugs. Charles O’Keeffe, a former Clinton ad- from the FDA, became Director of MDD in 1998. visor and later President of the U.S. company He would play a crucial role in the CRADA develop- Reckitts Benckiser Pharmaceuticals, has explained, ment, including in the face of disappointment with “You had to jointly defend the class of drugs, to LAAM’s outcome.a keep the agonist/antagonists where they were.”83 The time was propitious for Reckitts, as well. The DEA followed the international convention Disappointed with its analgesia business, the com- scheduling, even if technically they could do pany had contracted out buprenorphine commer- otherwise. Internationally, buprenorphine propo- cialization to numerous companies worldwide and nents fought to put buprenorphine under the had abandoned ethical drug development in the less restrictive Psychotropic Convention, arguing early 1980s.63 John Lewis moved to Bristol Uni- that pharmacological effects and dependence lia- versity, where Reckitts funded some pharmacology bility were distinctly different. Domestically, the research. The company’s reluctance to enter the ad- DEA tried to reschedule buprenorphine three diction therapeutics arena reflected a more gen- times. eral attitude among pharmaceutical companies that But the shift from research to industrial drug analgesics might, as Bigelow put it, be “tainted” in development for addiction treatment took off at the eyes of prescribers and pain patients if also used the intersection of two trajectories: formal inter- for addiction.72 Methadone, for instance, had found est on the part of NIDA and a change of orien- little use as a pain medication. As Chris Chapleo, tation within Reckitts. In 1989, the U.S. Congress now Reckitt & Benkhiser Director of Buprenorphine mandated that a Medications Development Pro- Business, recalled, Reckitts was under pressure at gram be established in NIDA. The following year, that time because of “misuse, abuse, diversion of NIDA established the Medications Development buprenorphine, the analgesic product” and its off- Division (MDD) to develop close working rela- label use to treat addiction. An estimated half of tionships between academia, the pharmaceutical the buprenorphine analgesic (Temgesic) supply in industry, and government agencies, including the France was being used off-label to treat addicts.67 FDA, so as to develop and evaluate addiction treat- Diversion resulted in buprenorphine, an unsched- ment medications to the point that they could uled molecule, being put into the Psychotropic Con- go through the FDA approval process. An In- vention in the late 1980s, with negative fall-out stitute of Medicine (IOM) report identified re- for the buprenorphine market. Doctors hesitated lapse prevention as the proper focal point for to prescribe scheduled drugs; sales of the buprenor- the MDD, but noted that the basic knowledge phine analgesic in France had dropped by 50% af- about the pathophysiology of protracted abstinence ter scheduling; patients had trouble obtaining it.67 and conditioned withdrawal remained rudimentary The International Narcotics Control Board (INCB) (p. 48).84 One of the MDD’s first priorities was to was mounting pressure to move buprenorphine get LAAM approved for an addiction treatment in- from the Psychotropic Convention to the more re- dication. This objective was accomplished in 1993 strictive Single Convention. Reckitts was also con- and LAAM was launched in the United States in cerned by two “Phase 1–like” studies conducted 1994. In 1993, MDD also approached Reckitts about formalizing their already existing mutual interest in developing buprenorphine for addiction treat- aSix European countries put LAAM on the market by ment. NIDA was interested in buprenorphine by 1997, but it was withdrawn beginning in 2001, following itself and in combination with naloxone (to prevent reports of severe cardiotoxicity associated with its use.88ci

134 Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c 2012 New York Academy of Sciences. Campbell & Lovell History and development of buprenorphine by a Belgian psychiatrist, Marc Reisinger using a years.b Once Suboxone and Subutex were launched, pharmacy-prepared buprenorphine compound postmarketing surveillance by an independent con- from the analgesic. Though these supported Jasin- tractor was subsidized by Reckitts as a requirement ski’s finding and showed that higher buprenorphine of the approval for marketing.92,c dosages were necessary for addiction treatment than Most NIDA-funneled resources contributed to for pain management, Reisinger’s studies involved the numerous clinical pharmacology studies be- off-label buprenorphine, which Reckitts felt it could tween 1980 and 1985, which compared various not condone.67 routes of administration and dosages, withdrawal, Despite Reckitts’s ambivalence, the company was and cross-tolerance. Later studies concerned induc- finally persuaded by Chapleo and O’Keeffe to tion, abrupt withdrawal, and short-term detoxifi- “remove the For Sale sign and develop buprenor- cation. In the 1990s, studies were extended to in- phine for the treatment of opioid dependence” clude dose omission schedules, pharmacokinetics, in partnership with NIDA, who “would be co- and buprenorphine for pregnant, opiate-addicted funding to ease the burden to Reckitts.”67 Reckitts women. These laid the groundwork for arguing that bought back its U.S. distribution rights but had buprenorphine was not merely a “substitute ther- to set up a U.S. company (Reckitts Colman Phar- apy,” in order to differentiate it from methadone. maceuticals),aswellasdevelopaninfrastructure Buprenorphine proponents, however, perceived (secure warehouse services, import permits, etc.) methadone regulation as an obstacle to pharmaceu- before entering into the CRADA. The agreement tical innovation for addiction treatment, an opinion was finally ratified in 1994. According to Reckitts’s the IOM 1992 Report also held.84 As the molecule negotiators, the company was swayed by argu- proved less toxic than methadone or LAAM when ments about “social responsibility” toward drug ad- ingested by nontolerant individuals, buprenorphine dicts85 and the ethics of withdrawing, buprenor- treatment was thought to require less oversight. And phine when patients were being treated with it for to compete with methadone, buprenorphine was pain.67 The following year, in the wake of a con- mainstreamed into medicine,67,85 which required taminated blood transfusion scandal and the AIDS amending the CSA requirement so physicians could epidemic among injecting drug users, France be- treat patients with a Schedule V narcotic. France had came the first country to approve buprenorphine normalized addiction treatment by allowing general (Subutex) for treatment of opiate dependence in practitioners to prescribe Subutex, as they would general medical practice, proving the national vi- ability of implementing the drug89 and prevent- ing Reckitts licensee Schering–Plough from losing bOriginally, Reckitts argued for orphan status on the its license because of off-label use of Temgesic. prevalence principle that the drug would affect a rare pop- France framed Subutex partly as harm reduction,90 ulation. The FDA rejected Reckitt’s prevalence estimate, which was based on the number of treatment-seeking ad- as would some Asian countries in the following 67 dicts, and not on the estimated number of addicts (treated decades. and untreated) in the U.S. According to O’Keeffe, Subutex In the United States, buprenorphine development and Suboxone were the first drugs ever designated orphan faced funding issues, scheduling, and potential reg- status on an economic basis.85 The economic principle ulatory problems, as well as competition with the argument enabled Reckitts to obtain exclusivity for seven methadone community. Public contributions to de- years, versus the 10 or 15 years they would have had under velopment eventually included millions of dollars in “normal” orphan drug status, making it one of the only contracts and grants. Reckitts obtained orphan drug orphan drugs based on this principle. c status for Subutex and Suboxone (the two buprenor- The study, which included 18,596 interviews with ap- phine medicaments for addiction treatment) in the plicants to substance abuse treatment programs, 8,194 surveys of federally certified physicians, as well as pub- CRADA,85 arguing the rarely used Cost Recovery licly available indicators of use and misuse of buprenor- principle; that is, that the company risked not re- phine and buprenorphine with naloxone shows a steady cuperating what it invested (buprenorphine is more increase in diversion and abuse from 2005 to 2009, al- 91 expensive to manufacture than methadone). The though at lower levels than methadone. Like studies in orphan drug designation freed the company from other countries, the authors suggested much diversion competition with lower-priced generics for seven was for therapeutic reasons.

Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c 2012 New York Academy of Sciences. 135 History and development of buprenorphine Campbell & Lovell any other treatment, in office-based practice.89 Ad- rights for Suboxone, Subutex, and Temgesic93,94 and dicts in many countries appropriated Subutex as assumed marketing in more than 30 countries in “a medicine for them.” 67 But NIDA, being a public Europe as well as the United States, Australia, New agency, could only provide the data used for schedul- Zealand, and South Africa and negotiated with other ing and testify regarding proposed laws; it fell to countries to buy back distribution rights before they Reckitts and the network of pro-buprenorphine re- expired. Reckitts moved toward being “a wholly- searchers and consultants to lobby for these changes. owned international franchise for Suboxone and Lewis, for example, spent much time in Geneva con- Subutex.”92 While treatment contexts are shaped vincing WHO to keep buprenorphine out of the by national and regional policy, as buprenorphine Single Convention and on a moderate schedule in circulates globally, it carries Western definitions of the Psychotropic Convention, as the outcome of this “addiction,” especially as an appropriate treatment decision would affect the DEA’s view. object for medicine, though not without encounter- In the United States, Reckitts took the legislative ing resistance in countries where addiction is heavily route, with O’Keeffe as architect of a policy with criminalized. complex technical and political repercussions, in- In the United States, Suboxone lost the ex- volving delicate negotiations with the FDA, DEA, clusivity afforded by its orphan drug status in SAMHSA, NIDA, Clinton administration, profes- October 2009. A year later, Reckitt–Benckiser Phar- sional groups, and politicians. The Drug Addiction maceuticals introduced Suboxone formulated as a Treatment Act (DATA) was finally passed in 2000. sublingual film, a patent-protected and “patient- It allowed office-based physicians who complete preferred delivery system,”... “to address the po- an 8-hour certification course to obtain a federal tential loss of up to 80% of the revenues and prof- waiver and treat opiate-dependent persons. Public its of the Suboxone tablet business in the year Law 109–460 (2006) extended the patient cap from following the launch of prospective generic com- 30to100forphysicianswithatleastoneyear’sclin- petitors.”95 The company’s overwhelming finan- ical experience with buprenorphine. Subutex (for cial success can be attributed to Suboxone, which opiate-dependent pregnant women and lactating accounted for 23% of U.S. revenues for Reckitt– women) and Suboxone received FDA approval in Benckiser in 2010.95 2002, but the DEA, which had expressed serious Historical tensions between maintenance and reservations before DATA 2000 passed, rescheduled abstinence, medicalization and criminalization, themfromCategory5toCategory3.86 and the complex interplay among patient choice, When DATA 2000 passed, the analgesic section provider authority, and regulatory constraints at Reckitts (by then merged as Reckitt–Benkhiser) structure the addiction therapeutics arena. Aimed as consisted of two people: O’Keeffe and Chapleo. In both a social and a pharmacological “fix,” buprenor- 2002, Johnson was brought in. Since that time, the phine must work at both levels if it is to work U.S. company has grown more than a hundredfold at all—that is, if buprenorphine is to shed the primarily due to the promotion of buprenorphine. stigma of methadone symbolically. Buprenorphine Reckitts explicitly sought to move addiction from for opiate dependence emerged from the long quest criminalization and toward medicalization through for a pharmacotherapy that worked not simply its concept of the “treatment space.” Reckitts’ inter- to block opiate effects but to attenuate them in national markets had previously focused on house- ways acceptable to addicted people. First explored hold products and nonethical drugs, mostly in the as a potential pharmacotherapy at the U.S. Pub- Commonwealth). Whereas in 1997, Reckitts had lic Health Service Hospital in Lexington obtained signed a 15-year Global Agreement giving exclu- the status of an FDA-approved opioid addiction sive worldwide distribution rights for buprenor- treatment in the 1970s, and Subutex and Subxone phine hydrochloride prescription products, includ- were launched in the United States almost three ing Subutex and analgesics, to Schering Plough,67 decades later. The difficulties of coordinating pub- essentially keeping buprenorphine’s growth at a dis- lic and private interests, local and global effects, tance, in the early 21st century. Reckitts remodeled changes in domestic regulatory mechanisms, and its “treatment space” vision as a global one. By 2010, perceptions of addiction and its treatment charted it had bought back much of its sales and marketing buprenorphine’s tortuous, 30-year path to FDA

136 Ann. N.Y. Acad. Sci. 1248 (2012) 124–139 c 2012 New York Academy of Sciences. Campbell & Lovell History and development of buprenorphine approval and market. Buprenorphine arose as a of Opiate Addiction in America. Harvard University Press, maintenance therapy at a time when addicts—like Cambridge, MA. other citizens—were expected to take personal re- 7. Acker, C. J. 2002. Creating the American Junkie: Addic- tion Research in the Classic Era of Narcotics Control.Johns sponsibility for health and healthcare, and where Hopkins University Press. Baltimore, MD. such decisions were seen as individual matters of 8. Memorandum from William C. White, Chairman of the choice and political entitlement. Reckitt’s new treat- National Research Council Division of Medical Sciences ment space dovetailed with this larger movement (DMS), to Lawrence B. Dunham, Executive Director of the of decriminalization, destigmatization, and normal- Bureau of Social Hygiene, discussing transfer of responsibil- ity for the Committee’s operations from the Bureau to the ization of addiction treatment, and buprenorphine NRC in 1928. Quoted in Eddy, N. B. 1973. The National Re- finally proved to be the “holy grail”—an office-based search Council Involvement in the Opiate Problem. National pharmacotherapy for opioid addiction. Academies Press. Washington, DC. 9. Report on the Research Plan from William C. White, Chair Acknowledgments of the Committee on Drug Addiction, to the Chairman of the National Research Council Division of Medical Sciences We obtained much of the basis for this paper (DMS) dated November 26, 1929. Quoted in Eddy, N. B. on May 18–19, 2009 at a workshop on the “His- 1973. The National Research Council Involvement in the Opi- tory of Buprenorphine” sponsored by the Univer- ate Problem. National Academies Press. Washington, DC. sity of Michigan Substance Abuse Research Center. 10. Appendix to the minutes of the Committee on Drug Addic- tion and Narcotics, 2 October 1947, p. 9. We would like to thank John Traynor, director of 11. Fishbein, M. 1931. The Indispensable Uses of Narcotics in the UMSARC, and James H. Woods for hosting this Practice of Medicine. Committee on Drug Addiction of the event. Participants included John Lewis, Andrew Division of Medical Sciences, NRC, and Division of Medical Cowan, C. Robert Schuster, Don Jasinski, Chris- Hygiene & US Public Health Service. Washington, DC. Ellyn Johanson, R. Ed. Johnson, Frank Vocci, and 12. King, M.R., C.K. Himmelsbach & R.S. Sanders. 1935. Di- laudid (dihydromorphinone). A review of the literature and Charles O’Keeffe. A.L. would like to thank Isabelle a study of its addictive properties. Publ. Health Rep.,Suppl. Feroni for more than a decade of exchanges and 113: 1–38. collaboration about buprenorphine. Some of the 13. 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