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The Rediscovery of Disulfiram

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New analyses rank disulfiram (Antabuse) among the most effective medications for alcohol use disorders. But why is it so underutilized? In this podcast we explore the history of this therapy – the oldest medication that is still in use in psychiatry.

Published On: 6/28/21

Duration: 25 minutes, 23 seconds

Transcript:

Some of the most effective treatments in psychiatry are also the most underutilized – lithium, clozapine, ECT…. But should we add disulfiram for alcohol use disorders to that list?

Kellie Newsome: Welcome to the Carlat Psychiatry Podcast, keeping psychiatry honest since 2003. 

Dr. Aiken: I’m Chris Aiken, the editor in chief of the Carlat Report. 

Kellie Newsome: And I’m Kellie Newsome, a psychiatric NP and a dedicated reader of every issue.

Dr. Aiken: Every week we open this podcast with that same intro – that we’ve been keeping psychiatry honest since 2003. That is when the first issue of the Carlat Report came out. But it’s not the only Carlat journal out there. We also have an edition for Child Psychiatry – launched in 2010; Addiction Psychiatry – 2013; Hospital Psychiatry – released this year in 2021; and we’re planning a Geriatric edition for 2022.

Kellie Newsome: But the Carlat Report that Dr. Aiken edits is for general psychiatry – or “all things psychiatric” as the byline says. But when something from the more specialized arms that the general psychiatrist needs catches our eye we try to include it, and that’s what happened this month with disulfiram, a medication for alcohol use disorders that is also known by its catchy trade name as Antabuse.

Dr. Aiken: Disulfiram has an unusual mechanism. It prevents the liver from clearing out acetaldehyde, the metabolite of alcohol that is responsible for the hangover effect. When patients drink even a sip of alcohol on disulfiram they can become violently ill, with nausea, vomiting, malaise, and headaches. 

In my training I was taught that disulfiram was not very effective because patients would just stop taking it if they wanted to drink. So I was surprised last winter when I came across a new meta-analysis of medications for alcoholism in patients with comorbid depression. The study looked at 18 classes of medications, and only 3 stood out with a statistically significant effect. They were:

  • The anticonvulsants (carbamazepine, topiramate, tiagabine)
  • A combination of naltrexone with a selective serotonin reuptake inhibitor
  • Baclofen, and
  • Disulfiram

But disulfiram’s effect size was much higher than the other medications, and it was the only medication to come up positive for both outcome measures – remission from alcohol use, and number of days abstinent from alcohol. 

This was unexpected, and I realized I had underestimated disulfiram’s utility. I called up one of our writers who is also an addiction psychiatrist, Stephen Wyatt, and he straightened me out on a few things. Disulfiram does work well, and not just in depressed patients – it often outperforms other medications in general alcohol use disorders. It’s certainly true that patients can stop the medication if they get the urge to drink, but satisfying that urge is not so simple because they need to wait 2 weeks after stopping it for the disulfiram interaction to clear out.

I was not the only physician who was underutilizing disulfiram – apparently this is a national problem. Some avoid it because they think it doesn’t work, others because they think it is too dangerous. There’s a myth out there that patients will drink impulsively on it and die. This has to do with a misunderstanding about disulfiram when it was first used in the 1950’s. Back then doctors thought that it worked through aversive conditioning, and that patients needed to experience the disulfiram hangover to overcome their alcoholism. Deaths have been exceedingly rare on disulfiram since that errant practice was ended, and Dr. Wyatt shared new dosing strategies that make the drug even safer.

But most importantly he set me straight on this. Deaths from alcohol related problems – from falls to liver toxicity – are through the roof in the USA. Among gen Xers, it’s the #1 cause of death, and for the country as a whole it’s the 3rd leading cause of preventable deaths. No self-respecting oncologist would withhold chemotherapy because the chemotherapeutic agents are potentially lethal. Cancer is a far more lethal disease, and alcohol use disorders are far more lethal than any of the treatments we have for them, disulfiram included.

Kellie Newsome: Yea, but our culture doesn’t view alcoholism the way they view cancer. Alcohol use disorders are still seen as something that the patient does to themselves, while cancer is a disease that happens to them. That’s just stigma, plain and simple, but I can see how that stigma rubs off on our prescribing practices. We don’t want to be responsible for bad outcomes when we’re treating something that much of the world doesn’t even view as a legitimate disease.

Dr. Aiken: There are a lot more myths and surprises about disulfiram, so check out our June-July issue for more. In this companion podcast we’re going to delve into the history of this unusual medication. Disulfiram is the oldest psychiatric medication still in use. It even predates lithium, which was first tested in bipolar disorder in 1949. Disulfiram began its clinical journey a few years before that, and it received FDA approval for alcohol use disorders in 1951. But we might never have discovered disulfiram if it weren’t for the automobile industry and the tires it requires. 

Kellie Newsome: Charles Goodyear had an obsession. The Connecticut inventor wanted to find a way to stabilize rubber. In the 1800’s rubber was harvested from tree sap in the Amazon rain forest. Its elastic nature held great potential, but rubber had a serious flaw. It cracked in the winter and melted in the summer. Charles spent 5 years and his family’s fortune trying to create a more resilient rubber, until a fateful day in 1839 when he accidentally dropped some rubber and sulfur on a hot stove. The combination of heat and sulfur transformed the material into a charred mass that most people would have thrown away. But Charles saw what he was looking for: A stronger rubber that held up well under extremes of temperatures. He called it vulcanized rubber, after the Roman god of fire. 

Goodyear set up a rubber factory in Naugatuck, Connecticut, a town just north of New Haven that soon became the rubber capital of the world. And the rubber he produced helped turn the wheels of the industrial revolution and later forged the tires that bear his name on many automobiles. The factories that built the industrial age depended on vulcanized rubber. It shaped the valves, belts and bands that turned the factory wheels, and it sealed the steam engines that powered them. 

Kellie Newsome:  But another chemical was getting in the way of that revolution – alcohol. Before the industrial revolution, most American drank alcohol regularly – day and night – it flowed in the halls of Congress and was a normal part of the workplace. Some people took it too far, but they were largely seen as a danger to themselves and pitied as the “town drunk.” But with the rise of factories that danger spread to the community. The factory could not run when essential workers stayed home with a hangover. And if they came into work intoxicated it was far worse – factory accidents could be deadly, and accidents were increasingly blamed on the excessive drinking that was woven into early American life. But factory life was stressful, and the saloon was a popular spot for workers to let off the steam of industrial life. And the ensuing intoxication wasn’t just causing problems at work, it was damaging their family lives as well.

Soon a loose coalition began to form among the wives of the heavy drinkers, the industrial leaders who depended on them, and the churches where they worshipped. This “temperance movement” gained political steam between 1860 and 1920, culminating in the legal prohibition of alcohol in America, Canada, and Scandinavia during the otherwise roaring 20’s.

Dr. Aiken: Prohibition of alcohol did not work, and most of those countries put an end to the experiment in the 1930’s after a decade of enforced abstinence. But another discovery was just around the corner that would pave the way to a chemically-induced enforced abstinence, and it took place in a rubber factory in Naugatuck, Connecticut, the same town where Charles Goodyear had first vulcanized rubber 100 years before.

Kellie Newsome: EE Williams was an industrial physician who worked for the rubber industry and looked after the health of their employees. In 1937 he noticed something unusual. Factory workers were becoming very ill with flushing, racing heart, nausea, vomiting, and headaches after drinking alcohol. Williams traced the problem to a new chemical in the vulcanization process. They had replaced the sulfur in Goodyear’s original formula with disulfiram. When disulfiram made its way to the worker’s liver, it blocked the enzyme that clears out acetaldehyde, a metabolite of alcohol that is responsible for the “hangover” effect. 

Dr. Williams noted that many of his patients gave up alcohol completely after experiencing this reaction, and speculated that disulfiram might be used as a kind of aversive cure for alcoholism. 

Clinical trials of disulfiram ensued, and in 1951 the FDA approved the medication for alcohol use disorders. 

Dr. Aiken: Factories are a rich source of psychiatric discoveries. The blue light blocking glasses we use for dark therapy in mania were developed to protect workers from the retinal-damaging lasers that are used to line up parts in factories. And a patient once shared this intriguing revelation about lithium with me. The patient had lived with unremitting bipolar disorder for 20 years, but she did have 3 years of recovery where she felt stable and in control. “What was going on then?” I asked. “That was when I was working at the battery factory.” 

Kellie Newsome: You mean, like, lithium batteries?

Dr. Aiken: Yes, they were, and so I prescribed lithium. She had a full recovery, and said she had felt the same sense of calm on lithium that she had in the battery factory.

Kellie Newsome: Who would have thought that one of the top medications for alcohol use disorders would have begun it’s life in a tire factory. But disulfiram may go back even further. The Irish psychiatrist Seamus P.M. MacSuibhne has discovered evidence of a disulfiram like reaction that early herbalists recognized as a cure for alcoholism. It’s kinda disgusting, so bear with me. When eels die in wine they produce a substance similar to disulfiram that also inhibits the breakdown of alcohol’s metabolite, producing aversive hangovers. This reaction was noted in a medical text from 600 ad, which said quote “When eels are killed in wine, whoever drinks it then develops a distaste for wine.” The same therapeutic advice showed up in a manual of medical herbs from the 1600’s, which says “Eels, being put into wine or beer, and suffered to die in it, he that drinks it will never endure that sort of liquor again’

Dr. Aiken: Learn more about how to use disulfiram in our online edition. And now for the word of the day… The Serotonin Transporter Gene

Kellie Newsome: SSRIs – Selective serotonin reuptake inhibitors – work by, while as the name implies – blocking the reuptake of serotonin into the neuron, and the gate where they block that re-entry is the serotonin transporter, also known as SERT or 5-HTT. And you need to know all 3 of those names because they are often interchanged. There’s another word you need to know on this subject – the SLC6A4 gene – which is the gene that codes for the serotonin transporter. The SLC6A4 gene is one of the most popular genes on pharmacogenetic test panels because it purports to tell us whether a depressed patient will respond to an SSRI or not. But that data is old news – it showed promise 10 years ago and has since failed to hold up its end of the hypothesis in study after study, although it has a small influence in some populations like older Caucasian males. 

The serotonin transporter did not evolve to receive SSRIs, however, and in next weeks podcast we’ll explore how the SERT gene influences everything from viral illness to personality in an interview with Vladimir Maletic.

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