29 June 2020

Historical paper on the development of opiate maintenance and links with AA.

'ALCOHOLISM' Clinical and Experimental Research Vol 15/No 5 Sept/Oct 1991

EDITORIAL Addiction as a Public Health Problem: Vincent P. Dole


WHEN I FIRST became involved in studies of addiction 30 years ago, a society dedicated to this topic would have had no place in organized medicine. The subject was not even considered in the curricula of medical schools. Back then we assumed that addiction simply was a sign of psychopathology. Drug abuse and alcoholism were regarded as shameful dependencies on chemical substances, used for illicit gratification and escape from reality. If the subject came up in discussion, a typical physician would say that addicts were morally weak: they needed discipline, not medical treatment and certainly not a medically prescribed drug. This negative attitude still has considerable force today in medical and political circles.

Times are changing, however. The existence of this society bears witness to the official recognition of addicts as sick persons, deserving serious study and medical treatment, when appropriate. I have seen some of the changes that have led us to this point and have had the privilege of learning from persons who are now legends. Let me describe these experiences.

In 1960 I was a laboratory-based investigator at Rockefeller University-busy in specialized work and insulated from the real world. I commuted to New York from a comfortable house with a big lawn and view of the water in Rye, New York. I worked during the day in a laboratory on the University campus, and returned home in the evening, usually reading and editing journal papers in transit. Sometimes I looked out of the window. Occasionally, to save time in the morning, I left the train at the 125th Street Harlem Station and continued the trip to my laboratory on the elevated Third Avenue trolley (now gone). Walking the short distance between stations on 125th Street and then travelling 60 blocks on the elevated trolley-in effect a moving aerial platform-I saw drugs being sold on the sidewalks, drunks sleeping in doorways, young men idling on corners, young women apparently available at a price, shabby buildings, and busy bars.

Of course I had been aware of social problems in the inner city. Then, as now, the media were filled with reports of gang wars, murders, rape, arson, drug abuse, police raids, etc. But being in the neighborhood made the problems real. Society was disintegrating in my own city, not in another world. Something very bad had happened to people in what not long ago had been decent neighborhoods. The community was sick. What should be done?

In the basic sense of the term, this was a public health problem. Young people had grown up in disorder, without adequate education or employment, and many were now addicted to alcohol and drugs. Streets were littered. Buildings had deteriorated. Successful persons had left the area. Drug abuse had made the victims of the process the vectors of further spread. Treatment would have to go beyond hiring more police. By analogy with epidemics of infectious disease, critical interventions were needed to halt transmission of drug abuse without adding to the damage, and do this with limited resources. In public health terms, where were the feasible points of attack on the epidemic of drug abuse?

Obviously, this would be more complicated than dealing with an epidemic of infectious disease, but it seemed reasonable to hope that a comprehensive public health approach could succeed, if backed by consistent political support. Large scale effective treatment programs were needed for persons already addicted, coupled with rational measures for prevention of new cases. However, it soon became apparent that this was too much to expect. A profound disruption of society, then as now, fragments a community into special-interest groups opposing each other. Elected officials become powerless to resist vocal minorities, or to institute needed reforms. And the medical profession, which should have provided leadership, was uninvolved.

Conversations with experts over the next several months showed confusion at all levels, from the technical details of treatment to the feasibility of social rehabilitation. However, by then I had become too deeply concerned with the problem to quit. At least I could examine one detail of the problem, namely the pharmacology of heroin addiction, to see if an effective large-scale treatment could be developed. Having no experience in the field, I needed help.

The event that changed my life was finding Marie Nyswander. I had read her book entitled “The Drug Addict as a Patient”, and it made sense. Moreover, I heard that she was the only doctor in New York who was willing to treat drug addicts outside of an institution. Other doctors were uninterested, or feared harassment by the Federal Bureau of Narcotics. I invited her to lunch at Rockefeller, expecting to meet a formidable lady.

To my surprise the lady who arrived was a gentle person, vibrantly alert but small in stature, soft spoken, shy in manner. What I remember most vividly about our first meeting is how tired she looked. Later I learned why. She was supporting herself as a practicing psychiatrist on Park Avenue while also counseling addicts in Spanish Harlem and fending off the bullies of the Federal Bureau of Narcotics. At that time even psychiatric treatment of addicts without prescription of any medication (she had surrendered her narcotic license to avoid entrapment) was considered suspicious by the Bureau. Nevertheless she persisted. Although she had had little long-term success in treating heroin users with psychotherapy, psychoanalysis (she was also a certified analyst), group therapy, and social services, she was determined to continue her work and find a better treatment. On the positive side, she had found the addicts to be cooperative patients who were desperately in need of help. What had sustained her during a decade of lonely struggle was a sense of injustice-sick people asking for help and being rejected-and the gratitude of the patients even when her efforts failed. She expressed the conviction that narcotic addiction is basically a medical problem, an organic disease needing an effective medicine to abolish the pathological craving for narcotic drugs before social and psychological help could be effective on a large scale. Coming from an experienced psychiatrist who had been trained at the Federal Treatment Center in Lexington, Ky, and subsequently had devoted 10 years of her life to the problem, this was persuasive. I invited her to join me in setting up a physiological study of heroin addicts in Rockefeller Hospital. She accepted. Three years later we were married and remained inseparable companions until her death from cancer 5 years ago.

During the first year of this work we had the good fortune to recruit a talented young clinician, Dr. Mary Jeanne Kreek, to participate in the testing program. We started where previous studies had stopped. Research on narcotic pharmacology in the Public Health Hospital (Lexington, Ky), although carefully conducted, had been incomplete. Short-term, toxic, and analgesic effects of various narcotic drugs had been well documented, but long-term behavioral pharmacology (which for narcotic drugs is quite different from the acute effects because of the development of tolerance and physical dependence) had not been adequately studied outside of a prison environment. In particular, the possibility of using a narcotic drug for maintenance of intractable addicts had been dismissed because earlier attempts to maintain addicts with morphine had failed. Knowing that the term “narcotic” comprises a wide range of drugs with significantly different properties, we decided to look further, testing other pharmacological agents in the narcotic category on addicted volunteers.

To our surprise we found that one of the tested drugs, methadone (but not any of several other narcotics that we tested), had a normalizing, rather than narcotic, effect on long-term administration at a constant dose. This paradoxical finding of a narcotic drug having a normalizing effect was not understood until some years later when the pharmacokinetic studies of Dr. Kreek showed that the blood level of methadone is stabilized by first pass removal of about 98% of an oral dose, thus in effect creating a slow-release depot. As the circulating drug is removed from blood by metabolism, it is replaced by dissociation of molecules absorbed in the depot. The nervous system adapts to the steady level of methadone in the blood, thus abolishing its depressant effects. The medication thereafter acts as a normal neuromodulator, apparently substituting for dysfunctional components. Repeated testing by many independent observers during the past 25 years has verified this functional normalization. A patient who is stabilized on an adequate, constant daily dose of methadone is alert, healthy, and responds normally to painful stimuli.

That is enough to say about the pharmacology of methadone in the present discussion, but before leaving the topic I must acknowledge the essential contributions made by many hundreds of dedicated physicians, counsellors, nurses, social workers, administrators, lawyers, volunteers, and ex-addicts who in their collective efforts translated a research finding into a treatment program. The original team deserves special recognition: Physicians: Drs. Joyce Lowinson, Robert Newman, Robert Millman, Elizabeth Khuri, Harold Trigg; Administrators: Ray Trussell and Detlev Bronk; Lawyer: Dona1 O’Brien; numerous ex-addicts who will remain anonymous; and the indispensable Herman Joseph, who is too versatile to characterize and too important to omit from this list.

Now to the second topic, alcoholism. In the early 1960’s I was honored (and puzzled) by an invitation to join the Board of Alcoholics Anonymous as a Class A (nonalcoholic) trustee. Under the Constitution of AA only seven nonalcoholic persons could occupy this position, while several hundred thousand regular members of AA had entered the Fellowship the hard way, by being alcoholics. I was afraid that they might have made a mistake, and so before accepting the position, I discussed my research with executives of the Fellowship and raised the question as to whether this appointment might involve a conflict of interest, or at least the appearance of one. Would it embarrass the Fellowship to have an investigator of chemotherapy for narcotic addiction included in the Board of AA? They insisted that they saw no problem since the objectives were parallel-namely providing the best treatment available to sick persons. They also pointed to AA’s Fifth Tradition, which states that the mission of AA is solely to help alcoholics, and firmly rules against taking a position on other issues. They were right. There never has been a problem in my association with AA, and my admiration for Bill Wilson and the dedicated AA members that I came to know has increased over the years.

Needless to say, I have gained far more from AA than the Fellowship did from me. It was my privilege to witness the healing force of personal service, group support and humility, while my only serious responsibility was to serve on a few committees and be an alert observer. As an organization, AA is the purest form of democracy. Major questions are submitted to the membership at the annual meetings of delegates representing all groups. Ultimately, questions of policy are resolved in a statement of the Group Conscience. The headquarters of AA, the General Services Office, is just what the name states. The secret of AA’s strength is service. It is a secret that certainly should be shared with the medical profession.

Throughout most of my time on the Board I continued to be puzzled by the original question: Why had I, specifically, been invited to serve? If a physician experienced in treatment of alcoholics had been needed for professional opinion, there were many persons with better qualifications than I. If an administrative advisor was sought, I would be near the bottom of any search list. My only qualification was caring. One answer gradually became clear: In the early years of AA Bill and the original trustees were acutely sensitive to the danger of the Fellowship being distorted by aggressive persons with dogmatic opinions. During my time on the Board, I never detected any sign of this happening, but perhaps that simply reflected the success of the Traditions in the mature organization, keeping the Fellowship on track. Anyway, I assumed that I had been brought in as sort of a smoke alarm, a canary in the mine.

A more specific answer, however, emerged in the late 1960s, not long before Bill’s death. At the last trustee meeting that we both attended, he spoke to me of his deep concern for the alcoholics who are not reached by AA, and for those who enter and drop out and never return. Always the good shepherd, he was thinking about the many sheep who are lost in the dark world of alcoholism. He suggested that in my future research 1 should look for an analogue of methadone, a medicine that would relieve the alcoholic’s sometimes irresistible craving and enable him to continue his progress in AA toward social and emotional recovery, following the Twelve Steps. I was moved by his concern, and in fact subsequently undertook such a study.

Until its closure this year, my laboratory sought an analogue of alcoholism in mice so as to be able to test potential medicines that could benefit human alcoholics. We failed in this, but the work is only begun. Talented investigators in other laboratories are working on various aspects of the analogue problem. With the rapid advance in neurosciences, I believe that Bill’s vision of adjunctive chemotherapy for alcoholics will be realized in the coming decade.

Now let me describe a coincidence that linked my work with Bill’s in an unexpected way, and perhaps explains my reaction to the scenes on the 125th Street 30 years ago. In Bill’s biography, he recalls a time in the winter of 1940 when the future of AA looked bleak. There was no activity in the newly opened club on 24th Street, and he was resting upstairs. Someone called up that a bum had come in, asking for Bill. Stumping up the steps was a stooped man with a cane who identified himself as a Jesuit priest. He said that he had come to meet Bill because of his admiration for the Twelve Steps. They were, he said, remarkably similar to the precepts of St. Ignatius Loyola, the founder of his religious order. As Bill’s biographer put it, “thus began a conversation that lasted 20 years.”

My association with AA came much later, but my contact with Edward Dowling, the priest in this story, antedated Bill’s meeting with him by 15 years. He was my classroom teacher in first year high school at Loyola Academy in Chicago in the mid 1920’s. At that time he was a slim and vigorous young novitiate with jet black Irish hair and an intense manner. Among other subjects he discussed ethical conduct, not as an abstract thesis, but as a practical obligation toward others, and as a service that brings its own reward.

In his subsequent busy career as a priest Father Dowling lived what he had taught, friend and advisor to people in trouble, to young families, to students, to alcoholics. I saw him only infrequently in later years, but remember most clearly the contrast between his continued intellectual force and his deteriorating health. Medically, he had severe rheumatoid spondylitis. He became progressively more stooped, white haired, limited in travel. Yet he did not even seem to be aware of his disability. He was too occupied with the problems of others.

Marie Nyswander, Bill Wilson, and Edward Dowling are no longer with us, but their inspiration remains. For each, life was a continuing Twelve Step. They cared for people who suffered and especially those with the double jeopardy of being sick and being rejected. They left a positive record of success in dealing with these problems.

It is my privilege, as their student, to greet the Society for Addiction Medicine, and transmit the expectations that they surely would have had for its future. They would have welcomed the strength and scientific discipline that you bring to the field. They would expect you to study and debate the technical details of treatment while being united in compassion for addicts. They would look to you for leadership that rises above special interests and prejudice. They would hope that you could lead the way to rational measures of prevention, and a variety of effective, nonpunitive treatments for various addictions. Certainly they would expect you to be concerned with the enormous public health problem of addiction: tens of thousands of drug addicts and hundreds of thousands of alcoholics who still remain untreated. It would be their fervent hope that you succeed.

From The Rockefeller University, New York, New York. Receivedfor publication May 8, 1991; accepted May 24. 1991 The Distinguished Science Lecture presented at the Annual Meeting of the American Society of Addiction Medicine, Boston, MA, April 19, 1991. Reprint requests: Vincent P. Dole, The Rockefeller University. I230 York Avenue, New York, NY 10021-6399. Copyright 0 I991 by The Research Society on Alcoholism. Alcohol Clin E.xp Re.\. Vol 15, No 5. 199 I; pp 749-752

2 February 2020

Fentanyl manufacturer and top executives jailed for unlawful marketing.

Fentanyl manufacturer and top executives jailed for unlawful marketing. Financial Times 24 January 2020


John Kapoor, who founded Insys Therapeutics, was sentenced to 5½ years in prison for Big Pharma crimes including the marketing of fentanyl, a product only approved in the USA for cancer break-through pain.  See news item on https://www.ft.com/content/a27bbc80-3d35-11ea-a01a-bae547046735

 “Opioid executive admits to ‘no morals’ ahead of prison term”

‘US pharmaceutical executives have been put on notice that they could be held criminally liable for fuelling America’s epidemic of opioid addiction, after the founder of the drugmaker Insys was sentenced on Thursday to five-and-a-half years in prison for masterminding a scheme to bribe doctors to prescribe a dangerous painkiller.’

Despite causing great satisfaction in some quarters, such prosecutions are unlikely to make much difference to opioid deaths currently.  In America, where addiction to prohibition is endemic, opioid use has now moved from prescription drugs back to the black market where we know regulation has no effect on price and little effect on availability. 

Comment by Andrew Byrne .. any replies best to ajbyrne@ozemail.com.au

Along the same line, relating to Mundipharma in Australia: Wall St Journal article.
“OxyContin Made The Sacklers Rich. Now It’s Tearing Them Apart.” https://www.wsj.com/articles/oxycontin-made-the-sacklers-rich-now-its-tearing-them-apart-11562990475  

And further: alleged actions denying life-saving buprenorphine treatment by hiking costs to patients and insurers. 
“Federal prosecutors said that starting in 2010, Indivior falsely marketed its film as being safer and less prone to abuse than cheaper tablet forms, illegally earning billions of dollars in a "nationwide scheme" to bill healthcare providers and insurers including Medicaid.”
https://www.npr.org/2019/07/11/740856948/reckitt-benckiser-agrees-to-pay-1-4-billion-in-opioid-settlement