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JOURNAL INTERVIEW

doi:10.1111/add.12711

Conversation with Walter Ling

trained there. I had a ‘J’ visa, which allowed me to attend residency, but required me to leave the country and not apply for re-entry for 2 years after my training; in any case, I was not eligible for licensing in Missouri and I had made a promise to my department back home. All that changed in ways completely unplanned and unanticipated. In Thailand, where I grew up, most people were Buddhists and they believed in karma. My parents came from Christian families, and my mother in particular always believed that I had a guardian angel looking after me. Looking back it is hard to argue with her. I started dating and eventually married May, a young schoolteacher who was volunteering at a nearby children’s hospital. By chance, my professor and mentor from home gained a year-long United Nations scholarship and decided to come to Washington University with his wife, also a physician. Soon we were more than teachers and students but close friends. Unbeknown to us, my mentor and his wife had decided that for the sake of our children’s future, May and I should stay in the United States.

In this occasional series, we record the views and personal experiences of people who have especially contributed to the evolution of ideas in the journal’s field of interest. Dr Walter Ling is a neurologist and psychiatrist, and is Director of the Integrated Substance Abuse Programs (ISAP) at the University of California, Los Angeles (UCLA), one of the foremost substance abuse research groups in the world. Dr Ling led pivotal clinical trials in the United States for all three of the only US Food and Drug Administration-approved opiate pharmacotherapies, levo-acetylmethadol (LAAM), buprenorphine and naltrexone, and is leading ongoing efforts for approval for sustained-release buprenorphine. Addiction (A): You have led the effort to bring nearly every medication for treating opiate addiction to market over the past four decades. Was it always your mission to develop medications to treat opiate addiction? Walter Ling (WL): Surprisingly, no. I had no plan to stay in the United States after my neurology and psychiatry training at Washington University in St Louis but was going to return to the Chulalongkorn University Medical School in Thailand. I knew nothing about drug abuse and had no ambition to become a researcher. I came to Washington University in St Louis because the chairman of physiology at Chulalongkorn University Medical School earned his PhD there and one of our neurosurgeons was © 2014 Society for the Study of Addiction

A: How did you get from St Louis to Los Angeles? WL: It is another unusual story—one of my attending supervisors at Washington University, Dr Herbert Rosenbaum, generously invited me to join his practice at the end of my residency. I said I could not accept because I could not be licensed in Missouri, and I had to leave the country on account of my ‘J’ visa. Soon after, through a Senate bill introduced by Senator Thomas Eagleton, later nominee for Vice-President to Governor McGovern in 1972, I received personal relief from the requirement to leave the country. The Attorney General of Missouri then ruled that foreign medical graduates could take the Missouri state medical licensing examinations. I did and was licensed. My mother thanked God and my guardian angel. I thanked Senator Eagleton and my attending supervisor, Dr Rosenbaum, who had much to do with my personal relief and the Attorney General’s ruling. Still, it was May’s firm conviction that we should raise our children in California, where there were more than only 50 Chinese families in town. So we came to Los Angeles, and I took a job at the Sepulveda VA Hospital. A: How did you get started doing research in Los Angeles? WL: Having been trained in both neurology and psychiatry, I was interested in the borderland between them— things such as dementia and other behavioral neurology. The Sepulveda VA Hospital was building a nursing home for geriatric psychiatric patients, and I was asked to come Addiction, 110, 14–18

Journal Interview

for a visit and give a talk. I had just finished a study on childhood depression, something the majority of the field thought not to exist, as depression was supposed to be the super ego punishing the ego, and children had no developed super ego. But of course children do get depressed, so Warren Weinberg (a leading child neurologist) and I conducted a study on childhood depression [1]. We set up the first diagnostic criteria, patterned after DSM-III, except that this was a decade before DSM-III actually appeared. You may recall that Washington University is often dubbed the birthplace of the DSM; so I gave my talk on childhood depression and was offered a job at the Sepulveda VA Hospital and took it. I did not know then that the VA had no children or adolescent services, but I suppose it did not matter. A: But how did you get from practising psychiatry to studying drug abuse? WL: When I arrived at the Sepulveda VA Hospital in the summer of 1971 the nursing home was still under construction, so I helped out on the general psychiatric ward. At that time, Sepulveda had one of the VA’s first methadone programs, and it was receiving heroin-addicted veterans coming home from Vietnam. One day, the Chief of Psychiatry and Research, Dr Anthony Brunse, called me to his office and said he needed a favor. The doctor on the methadone ward had left suddenly, and Dr Brunse asked me to take over the ward temporarily, while he was away vacationing and attending a conference in Hawaii. I said I would; I was not doing anything all that exciting anyway. I had not treated any heroin addicts before and I knew nothing about methadone but in the 3 weeks that followed, I learned much more than methadone detoxification. I learned to be comfortable with some of the most difficult patients, to do what I could with them and for them and, most importantly, I learned how to rely upon everyone around me to make a successful team. Still, it was a relief when the 3 weeks drew to a close. What I did not realize was how much I had become used to the patients and the staff, and them to me. When Tony returned, he said I should know that the entire ward staff had petitioned him to keep me on as head of the service. To help me make up my mind about the job, he suggested I spend a week in Palo Alto with Dr George Krieger, then advisor to then California Governor Ronald Reagan on alcoholism and drug abuse. Dr Krieger taught me to see the addict behind the addiction and I became interested in the broken life stories of the addicted patients and how to make them whole again. I returned to Sepulveda, took on the methadone program and interviewed the next 100 patients who came to the service. I wanted to find out what they were really like psychiatrically. Before then, the only systematic psychiatric evaluations of heroin addicts were from studies using MMPI (Minnesota Multiphasic © 2014 Society for the Study of Addiction

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Personality Inventory) testing; there were apparently no data from clinical interviews, let alone the use of any diagnostic criteria. From those first 100 patients I interviewed, with help from a couple of young colleagues, I discovered that the general assertion that addicts are all sociopaths was mostly wrong [2]. Fewer than one-half fulfilled the diagnostic criteria of antisocial personal disorders. A full quarter of them had diagnosable alcoholism and while many appeared depressed, few had a depressive disorder based on diagnostic criteria. Many patients had anxiety disorders, but schizophrenia was rare among heroin addicts. A: What was the state of methadone treatment at the time? WL: In those early days it was routine to put every patient through a program of detoxification first. Patients were started on 30–40 mg of daily methadone and brought up to where they were not experiencing many withdrawal symptoms for a few days; their dose was then gradually decreased ideally to zero, which was rare. The great majority of patients had more and more withdrawal symptoms; it became clear that they needed to remain on methadone, so were discharged to the out-patient methadone clinic. It is amazing how little we knew then, and how little we realized what we did not know. A: How did you start conducting treatment research? WL: In 1972, Dr Samuel Kaim, Director of the VA Drug and Alcohol Service, and Dr Jim Klett, Chief of VA Central Neuropsychiatric Research Center at Perry Point, came to visit. They had been asked by Dr Jerome Jaffe, recently appointed Drug Czar by President Richard Nixon, to organize a multi-center LAAM versus methadone study and were looking for investigators. After explaining what they had in mind they asked whether I thought we could do such a study and I said I did not see why not. I did not know then that, except for one VA doctor in St Louis who said ‘maybe’, I was the only person from all the VA methadone programs from New York to California to say I thought we could do it. They asked if I knew of anyone else who might feel the same and I mentioned Dr Charles Charuvastra, who had spent the last 6 months of his residency with me at Sepulveda and was at the time running the methadone program at the Brentwood, California, VA Hospital. We called Charlie and he agreed, and so became the pilot sites for what became known as the VA Cooperative LAAM study [3]. When Dr Kaim retired from the VA I was asked to serve as the study Chair. Shortly afterwards, I was asked to chair a 13-site multicenter study transferring methadone-maintained patients to LAAM, known as the Special Action Office for Drug Abuse Prevention (SAODAP) LAAM study [4]. These two studies provided much of the pivotal data for Addiction, 110, 14–18

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LAAM’s approval some 20 years later. I was about the least experienced person in addiction pharmacotherapy research to lead the SAODAP study, but these studies allowed me to get to know and learn from the leaders in the field, people such as Herb Kleber, Chuck O’Brien and Ed Senay. All have become life-time friends. Most luckily for me, Jim Klett took me under his wing and taught me everything I know about research. A: How did those early research experiences help you become the researcher you are? WL: As I was saying, Jim Klett was, and still is, my great mentor. During the early LAAM trials Jim would meet with me every couple of weeks somewhere between Baltimore and Los Angeles and we would go over piles of computer printouts. Jim showed me everything about clinical trials, from study design to data collection to the interpretation of results, while I tried to make sense of fluctuating laboratory values, adverse events and safety monitoring. It was like going through a post-doc training program. I had no idea what people learn in a post-doc research program, but years later I would hear about this innovative research idea or that new method and remember that it was exactly what Jim Klett had told me over a beer or a bowl of gumbo years ago. A: How does this systematic approach affect your study designs? WL: Jim Klett was a minimalist, and I learned from him to keep things simple. For example, the 50 mg, 100 mg methadone and 80 mg LAAM study was to be a longterm study, including monthly laboratory evaluations throughout, so Jim suggested that we plan a 40-week trial with laboratory work every 4 weeks. The design was used in several subsequent studies, and for a time it became the standard protocol for all long-term medication trials. Later people would ask us how we came to design those protocols; we told them it was because 40 divided by 4 was 10 and we could do all the calculations in our head. Keep things simple. A: How did you begin to lead medication studies? WL: I believe Jim Klett recommended me to chair the VA LAAM Cooperative Multi-center study when Dr Kaim retired from the VA, probably because I was a hard worker and a pretty decent student; I cut my teeth on that trial, so to speak. It turned out to be the first multi-center placebocontrolled trial of its kind. Shortly thereafter I took on chairing the 13-site SAODAP LAAM study and by the time we got to the naltrexone multi-center study I had become quite an old hand—I led more multi-center medication trials in drug abuse than anyone I knew. Of course I was not alone, and Jim Klett knew everything and everybody who knew anything about clinical trials. Jim not © 2014 Society for the Study of Addiction

only taught me how to conduct clinical research, but he also introduced me to his friends, all leaders in their own areas of research. I learned psychopharmacology and research designs, study forms and instruments, and all sorts of other research tricks of the trade and trade secrets from people such as Leo Hollister, Jerome Jaffe, John Overall and Danny Friedman, to name just a few. You cannot imagine how much you can learn tagging along for an evening with those giants. It is like being enrolled into half a dozen post-doc training programs all at once. Meanwhile, I also got better and better just by doing. A: How did you develop your ideas in measuring outcomes in your clinical trials? WL: The prevailing method to look at study results at the time was the percentage of positive urines. Right away Jim and I decided that a positive urine at the beginning of a treatment probably does not have the same meaning clinically as one at the end of treatment, so we tried to give different weights to positive urines according to how long the patient had been in the trial, giving more weight to those in the later part. We also began to factor-analyze patient reports of symptoms and side effects, grouping them into an underdosing factor, overdosing factor, somatic factor, and so on. We were not happy with having to impute the value of missing urines because we mostly assumed that patients must be using illicit drugs if they failed to give a urine sample, but we were not really sure—so we were looking for other ways to measure how patients perform in a trial. You never know who will give you the best ideas. As I recall, Jim Klett’s wife, Shirley, who was a research psychologist and statistician, was the one who said to us: ‘Instead of arguing about what a missing urine means, why don’t you just count the negative ones instead?’. That led us to the Treatment Effectiveness Score (TES) [5] by calculating the percentage of negative scheduled urine samples a patient provided over the total number of scheduled urines to be collected. In this way, a patient who provides a ‘clean’ urine every scheduled time gains a score of 100 and everyone in the study is given a score between 0 and 100. People argue that what we did amounted to assuming missing urines to be positive, but the idea of TES is more than counting clean urine; it implies a degree of treatment adherence: the degree to which a patient follows through with his commitment to participate in the program or the trial. To gain a point he has to come to the clinic as scheduled and give a urine sample when asked, and the urine sample has to be negative for illicit drugs. The TES thus documents the successful completion of some rather complicated behaviors of clinical importance. Its strength is in its simplicity. Addiction, 110, 14–18

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We also had the idea of a moving time-frame that counts the number of clean urines within a defined treatment window, emphasizing the last urine result. That helped us to track how patients performed during the trial. The development of the Clinical Opioid Withdrawal Scale (COWS) [6] came much later as part of our work with buprenorphine. It is gratifying to see how widely used it has become. Even more recently I have been advocating the idea of a quick, yet comprehensive, measure of treatment effectiveness by asking the patients directly, using a few simple guides that reflect their drug use and other life changes. We called it the Treatment Effectiveness Assessment (TEA) [7]. All these came from another lesson Jim Klett taught me: while you are conducting research, you might as well think about how you can conduct it a little better. A: Whatever your approach, you have been involved in the development of every major medication for opiate addiction that is marketed currently in the United States. WL: As you know, it took nearly 20 years for LAAM to gain federal Food and Drug Administration (FDA) approval but much shorter than that to have it disappear from clinical use. Fortunately, I think the development of buprenorphine has been more gratifying not only as an effective medication from the patient’s perspective but also as a life-changing agent for the treating physicians. Its true significance is that it gives doctors a chance to change themselves so that they can help change the lives of their patients, as buprenorphine, unlike methadone and LAAM, allows physicians the opportunity to deal with their addicted patients in their usual and customary practice environment. If you look at the series of buprenorphine trials we have carried out with the National Institute on Drug Abuse Division of Medication Development earlier and with NIDA’s Center for Clinical Trials Network more recently, you can see a thread running through all of them. Each study built on the one before to keep improving the use of buprenorphine in the care of opioid-addicted patients. I think my years at the Washington University had taught me systematic thinking, and made me a good student under Jim Klett’s tutelage. We may not have performed many studies, but I think almost all the studies that we did perform were pretty well thought out in terms of what questions we wanted to answer and how to answer them. That did not mean we were always successful, but we did not perform a lot of fuzzy studies. A: From your vantage, what is next for medications for opiate addiction? WL: There will always be a need for an opiate, and I am afraid it may always come with the smiles and frowns of its two faces; that is why opiates are called Janus drugs. © 2014 Society for the Study of Addiction

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Buprenorphine’s discovery was part of the search for a ‘non-addicting opiate’. The idea of separating the moodaltering aspects of opiates and the pain-relieving aspect sounds good, and sometimes we think we are almost there. However, I am not really sure that even if we do find an opiate that both reduces pain and has no psychological reinforcing effects that patients would actually want to take it. We will not know for certain until we have such a medication. A: What happened with long-acting buprenorphine? WL: Take, for example, Probuphine. Nothing is perfect, but you can weigh the pros and cons. At this moment, a medication such as Probuphine would probably do more good than harm, and that is why I am interested in it. I am not sure what will happen next, but it is true: there is always more room for developing better medications. In the long term, any medication that helps take the addict’s mind off his or her daily dose of opioids, prescribed or otherwise, is a good thing. It frees patients from their daily preoccupation with their medications so they can focus on doing different, non-drug-associated things so their lives can turn out differently. Meanwhile, if it also keeps someone from dying from overdose every now and then, so much the better. A: As you spoke of earlier, not even methadone is a perfect medication. WL: Not only are there no perfect medications, there are not even good medications or bad medications. There are just the right ways and the wrong ways to use a medication. One thing we know about treatment for opiate addiction is that short-term treatment does not work. The most common outcome of detoxification is relapse. You have heard me say a thousand times that detoxification may be good for a lot of things but staying off drugs is not one of them. When we say ‘substitution treatment’, we are not really talking about substituting one drug for another; we are talking about substituting a drug memory with a non-drug memory, and that takes work. It takes hard work to make a new non-drug life. People often ask me how long someone has to be on methadone or buprenorphine. When can they get off? My answer is always the same. Get a life, and then get off the medications. A: Can you talk a little about the place for behavioral approaches, including 12 Steps, in treatment? WL: I have always said ‘talk is cheap, and it works’. There is nothing wrong with the 12-Step program or any other behavioral approach, but it is not good to be too hung up on any specific approach to the exclusion of others. Addiction is a disease of extremes and any treatment approach carried to the extreme, becoming the only way, Addiction, 110, 14–18

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is not good. By the way, it is wrong to call 12-Step a self-help program; it is anything but self-help. It is a mutual help program and it depends on the relationships developed within the group to be successful. As Dr Alan Leshner put it, whether you use a medication or talk therapy (actually I think it is more like listening), you are doing the same thing. You are trying to change the brain and if you change your brain, you change your life, but there is no single way. In the end, every life is a story, and every addicted life is a broken story. We have to listen and find out where the story went off track and do our best to help make it whole. Language is our currency. That is our job. A: What are some of the other lessons you have picked up about medication research? WL: One thing about clinical research is that you are dealing with real patients. In one respect research deals with plurality and generality, but in another respect clinical research deals with singularities and individuals. You get to know your research subjects and they get to know you. One big plus I think you gain from conducting research with addicts is that you learn to work with some of the most difficult patients you will ever see, and no patients will ever scare you after you have learned to be comfortable with them. The truth is that addicts and I live in the same world; they know prejudice, rejection and isolation, things I can identify with. Another thing is that when you treat them as if they are real people, they are genuinely grateful. Addiction research makes you realize how much you are interdependent with the people around you. You learn not to take yourself or your work too seriously; you learn to treat everybody as equals, to take advantage of what everyone can contribute and build a collaborative working team. I think this is more so in the addiction field than in others. A: As you say, your career is a story of how you found your luck. WL: Every step of my way I have been lucky. My entire career in research was unplanned; every step of it was an accident. For example, I came to Los Angeles to give a talk

© 2014 Society for the Study of Addiction

on childhood depression, not knowing that the VA did not treat children. I think we should not try to be too sure what we will get before we start something. If we insist on knowing what is at the end of the rainbow, we deprive ourselves of the unseen miracles along the way. I think it was Gilbert Proesch who said: ‘We try not to have ideas, preferring accidents’. My only guide has been not to do anything that would make me feel sheepish if someone told my mother about it. Other than that, accidents are what got me here. Thank God, and my mother.

Note The opinions expressed in this interview reflect the views of the interviewee and are not meant to represent the opinions or official positions of any institution or organization the interviewee serves or has served.

References 1. Ling W., Oftedal G., Weinberg W. Depressive illness in childhood presenting as severe headache. Am J Dis Child 1970; 120: 122–4. 2. Ling W., Holmes E. D., Post G. R., Litaker M. B. A systematic psychiatric study of the heroin addicts. Proc Natl Conf Methadone Treat 1973; 1: 429–32. 3. Ling W., Charuvastra C., Kaim S. C., Klett C. J. Methadyl acetate and methadone as maintenance treatments for heroin addicts. A Veterans Administration cooperative study. Arch Gen Psychiatry 1976; 33: 709–20. 4. Ling W., Klett C. J., Gillis R. D. A cooperative clinical study of methadyl acetate I. Three-times-a-week regimen. Arch Gen Psychiatry 1978; 35: 345–53. 5. Ling W., Shoptaw S., Wesson D., Rawson R. A., Compton M., Klett C. J. Treatment effectiveness score as an outcome measure in clinical trials. In: Chaing N., Tai B., Bridge P., editors. Medication Development for the Treatment of Cocaine Dependence: Issues in Clinical Efficacy Trials. Rockville, MD: National Institute on Drug Abuse; 1997, pp. 208–20. 6. Wesson D. R., Ling W. The Clinical Opiate Withdrawal Scale (COWS). J Psychoact Drugs 2003; 35: 253–9. 7. Ling W., Farabee D., Liepa D., Wu L. T. The Treatment Effectiveness Assessment (TEA): an efficient, patient-centered instrument for evaluating progress in recovery from addiction. Subst Abuse Rehabil 2012; 3: 129–36.

Addiction, 110, 14–18

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Conversation with Walter Ling.

In this occasional series, we record the views and personal experiences of people who have especially contributed to the evolution of ideas in the jou...
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