A Brief Excerpt About a Personal Hero: Marie Nyswander

Treating opioid use disorder is one of the great joys of my life. Treatment is profoundly effective, and it’s incredible to see someone’s life change when treatment is initiated. But the crucial insights that guide treatment are not intuitive, and the pioneers who discovered these principles have largely been forgotten in our collective memory. Today, we’ll discuss a moment in the development of agonist therapy: the careful prescription of long-term, high-dose opioids to people who cannot stop using opioids [1].

(To the uninitiated, agonist therapy may seem irresponsible. You give people with a heroin problem massive doses of opioids? Yes, we do! And it is completely life changing. Methadone and buprenorphine–the most common medications–have saved untold lives [2]. But there’s much more to life than not dying; people on agonist therapy generally live healthy, happy, productive, normal lives. It doesn’t work for everyone, but it’s one of the most effective treatments for a chronic medical problem ever developed. It’s an uncontroversial intervention among addiction medicine doctors around the world. I’ve never encountered a philosophical or data-driven argument against this form of treatment that I find even marginally compelling.)

I’m excited to share with you an excerpt from “A Doctor Among the Addicts,” by Nat Hentoff [3]. This 1968 volume is now out of print, but it offers a rare glimpse into the life of one of my personal heroes, Dr. Marie Nyswander. Nyswander spent almost two decades developing a reluctant expertise in addiction before meeting a collaborator in Dr. Vincent Dole. Their work–which should have won a Nobel Prize [4]–ultimately resulted in the discovery and empirical validation of methadone as a profoundly effective treatment for people with opioid use disorder. In this passage, Hentoff and Nyswander describe the first two patients treated, and the insight that led to methadone.

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To help prepare the hospital staff, including the nurses, for the new work, Dr. Nyswander brought addicts to the [Rockefeller] Institute during the month before the project was to begin. There were conversations with them, and afterward the nurses, for whom Dr. Nyswander has a deep admiration, did a good deal of reading about addiction on their one. It was then decided to admit two “hard-core criminal addicts.” Elaborate security precautions were taken in an isolated wing of the hospital. Safety glass protected hospital medication, additional locks were provided, the security personnel was aletrted, and an outside security agency was also hired.

In the January, 1967, issue of The Bulletin, a publication of the New York State District Branches of the American Psychiatric Association, Dr. Nyswander described the start of the research. “The first patient,” she wrote, “was a 34-year-old single male of Italian extraction, and the second, a 21-year-old single male of Irish background. Both had a history of drug use for eight years, had spent several years in prison for possession of drugs and theft, and had made numerous attempts to get off drugs by detoxification in voluntary hospitals and in the federal hospital in Lexington. One patient had gone to California in his desperation to remain drug-free. Both patients had tried psychotherapy. Both had dropped out of high school in the first year. The I.Q.’s of the patients, as measured on the Wechsler-Bellevue Intelligence Scale, were 120 and 124.”

These first two addicts came in, Dr. Nyswander later explained to me, “because they knew they’d get drugs and because they wanted to get off the street for awhile. We were given a free hand by the Institute, and I had the watchful, perceptive, analytical guidance of Dr. Dole. The best thing that ever happened in this field was his getting into it; the success of this project rests squarely on him, in my opinion. There were no problems with the Narcotics Bureau because we were working in a hospital. Dr. Dole told me, ‘Marie, nobody’s holding you back now. You can do anything you want to do.’ And I suddenly realized that I wasn’t at all sure that I knew what I wanted to do. I’d heard the term ‘legalized drugs’ all these years, and used it myself, too, but now I had to ask: What did it really mean? What medical procedure?

“Well, we started the addicts on morphine, a quarter of a grain four times a day. In three weeks, in order to keep them comfortable, we had to go up to eight shots a day of an increased dosage, a total of ten grains a day. Obviously, it was going to be impractical to devise a maintenance program on morphine. Also, on morphine the patients were rendered practically immobile. Much of the time they sat passively, in bathrobes, in front of a television set. They didn’t respond to any of the other activities offered them. They just sat there, waiting for the next shot. One thing I did find out was that there were no problems with the patients. They cooperated beautifully and honestly. They had no desire to go out and cop heroin, because they didn’t have to. They didn’t need any sense of adventure in connection with their addiction.

“But,” she continued, “there they sat, their interests ebbing and flowing in rhythm with the morphine injections. I was confronted with an abysmal lack of knowledge of what to do next. And then there was an accidental circumstance. We switched them to methadone, a drug that had been synthesized during the Second World War by German chemists looking for inexpensive morphine substitutes. At the end of the war, the American government seized the formula, along with thousands of others, to be turned over to American drug manufacturers as an ‘open patent.’ We knew that it was a very effective pain-killer, that it had long-acting properties and minimal withdrawal symptoms. We also knew that it could be substituted for any other kind of narcotic.

“The accident was this. We wanted to reduce the huge daily doses of morphine without subjecting the two patients to severe withdrawal symptoms. Methadone was a way to do that, but because they had been on such high dosages of morphine, we had to put them on equivalently high dosages of methadone, more than twice as large as is usually given when methadone is used to withdraw people from heroin. And to keep them comfortable during the next few days, we gave them bigger and bigger amounts of methadone. What we then discovered would probably not have been apparent if those dosages of methadone had been a lot less, as they have been in some other, not so successful experiments with methadone. From that point, my life changed, and the addicts’ lives changed.

“I was still staggering back from my failure with morphine, and it was Dr. Dole who realized what was happening in front of us. Striking alterations in behavior and appearance were taking place in the two patients. The older addict began to paint industriously and his paintings were good. The younger started urging us to let him get his high-school-equivalency diploma. We sent them both off to school, outside the hospital grounds, and they continued to live at the hospital. Neither of them–although both of them had every opportunity–copped heroin on the outside. From two slugabeds they turned into dynamos of activity. We gave them all kinds of tests while they were on methadone. We found out that methadone blocked out all other narcotics. They couldn’t feel the effect of another narcotic while they were on methadone. Accordingly, there was no craving for heroin. We found out that methadone could be given only once a day, and that sometimes the patients were so busy they actually forgot to take it. So, in addition to freeing a patient from the need to think about drugs for twenty-four hours a day, it appears that methadone gives him another eight-hour leeway. And whatever withdrawal symptoms occur during that leeway are very mild. We confirmed the fact that the drug could be taken orally and we first put it in orange juice. As for tolerance, there was no escalation problem. The dosage remained stable. In addition, we did endless medical studies–G.I. tests, bone marrow tests, blood studies, X-rays, motor-coordination tests, psychological tests. Methadone had no deleterious effects anywhere.

“And the behavioral changes continued to take place at a dazzling rate. One addict who later went on the program told a meeting of psychiatrists, ‘When you’ve got the craving, when you have to keep scuffling for drugs, you can never complete anything. And so you never know what you can do.’ That’s why all addicts tend to behave alike while they’re stealing and lying and figuring out ways to cop. But when they’re released from the craving and the scuffling, they begin to find out who they are, and so do we. It’s tremendously moving to watch them change.

“One example of the change in addicts’ behavior that has held up through the entire first three years of research has had to do with their staying in the hospital during the initial stage of the methadone treatment. Addicts have been notorious hospital dropouts, rarely staying long enough to finish most treatment plans. And often hospitals have dismissed them because of their antisocial behavior. Many of our patients had had such discharges, and few had finished earlier attempts at treatment, whatever they were. But under methadone, all our patients have remained in the hospital the full six weeks except for a few working men or women whose children were being cared for by relatives. In those cases we did give them an earlier discharge.

“As for our first two patients, both completed the requirements for their high-school-equivalency diplomas, but the younger one also wanted an unqualified high school diploma. In eighteen months he worked through three years of the high school curriculum, including mathematics, physics, English, history, and Spanish, with A grades. He went on to an engineering college on a full scholarship. The older patient completed a two-year course at horticulture school and is working in a greenhouse. They continue to take methadone and come to the hospital for weekly supplies.”

Footnotes

[1] In the United States, we sometimes use the terminology “dispense” instead of “prescribe.” Dispensing usually describes the direct provision of opioid doses through a methadone clinic, while prescribing typically means a set number of doses from a pharmacy. There is endless regulatory minutia around these terms, but “prescription” is much easier for most people to understand, so I’ll use it here.

[2] It’s hard to estimate the actual number of lives saved by agonist therapy, but it’s easy to estimate at least a 6-figure number for the United States alone.

[3] I hate the term “addict,” but it was normal to use in the time period. Modern guidelines for language in medicine wisely recommend that people not be defined by a problem they experience. “Correct” language can sometimes put us on a euphemistic treadmill or lead to pedantic bullshit, but I like this particular change.

[4] Nominees for the Nobel Prize are kept private for 50 years. However, the prize in physiology or medicine doesn’t have published data after 1953–so we’re actually missing 72 years of data at this point. I hope we’ll find Nyswander and Dole among the nominees when we have data!